Hydrogel compositions demonstrating phase separation on contact with aqueous media

ABSTRACT

A composition is provided, wherein the composition comprises a water-swellable, water-insoluble polymer or a water-soluble polymer, a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding to the hydrophilic polymer. The composition also includes a second water-swellable, water-insoluble polymer that provides for a phase separating film forming composition. Active ingredients, such as a whitening agent, may be included. The composition finds utility as an oral dressing, for example, a tooth whitening composition that is applied to the teeth in need of whitening, and removed when the degree of whitening has been achieved. In certain embodiments, the composition is translucent. Methods for preparing and using the compositions are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/848,538, filed May 17, 2004, now U.S. Pat. No. 8,541,021, which is acontinuation-in-part of U.S. patent application Ser. No. 10/442,020,filed May 19, 2003, now abandoned, which is a continuation-in-part ofU.S. patent application Ser. No. 10/359,548, filed Feb. 5, 2003; whichis a continuation-in-part of U.S. patent application Ser. No.10/137,664, filed May 1, 2002; which claims priority under 35 U.S.C.§119(e)(1) to U.S. provisional Patent Application Ser. No. 60/288,008,filed May 1, 2001.

TECHNICAL FIELD

This invention relates generally to hydrogel compositions. Moreparticularly the invention relates to hydrogel compositions useful asdressings or protectants and for administering a wide variety of activeagents to skin and mucosal tissue such as the mouth, including toothwhiteners.

BACKGROUND

Discoloration of the teeth occurs widely in society, and is estimated tooccur in two out of three adults. Dental discoloration is considered anaesthetic flaw or defect, and can have negative consequences in anaffected person's life by causing self-consciousness, and eveninhibiting smiling. Tooth discoloration can be particularly distressingor troublesome in situations and professions where showing clean andwhite teeth is essential.

A tooth is comprised of an inner dentin layer and an outer hard enamellayer that is slightly porous. The outer layer is the protective layerof the tooth. The natural color of the tooth is opaque to translucentwhite or slightly off-white. Staining of teeth arises as a result ofexposure of compounds such as tannins and other polyphenolic compoundsto the teeth. These compounds become trapped or bound to theproteinaceous layer on the surface of teeth, and can penetrate theenamel and even the dentin. On occasion, staining can arise from sourceswithin the tooth, such as tetracycline, which may become deposited inthe teeth if administered to an individual when young.

Surface staining can usually be removed by mechanical tooth cleaning.However, discolored enamel or dentin is not amenable to mechanicalmethods of tooth cleaning, and chemical methods, which can penetrateinto the tooth structure, are required to remove the stains. The mosteffective treatments for dental discoloration are compositionscontaining an oxidizing agent, such as hydrogen peroxide, that iscapable of reacting with the chromogen molecules responsible for thediscoloration, and rendering them either colorless or water-soluble, orboth.

Consequently, tooth whitening compositions generally fall into twocategories: (1) gels, pastes, or liquids, including toothpastes that aremechanically agitated at the stained tooth surface in order to affecttooth stain removal through abrasive erosion of surface stains; and (2)gels, pastes, or liquids that accomplish a tooth-bleaching effect by achemical process while in contact with the stained tooth surface for aspecified period, after which the formulation is removed. In some cases,an auxiliary chemical process, which may be oxidative or enzymatic,supplements the mechanical process.

Some dental compositions such as dentrifices, toothpastes, gels, andpowders contain active oxygen or hydrogen peroxide liberating bleachingagents. Such bleaching agents include peroxides, percarbonates andperborates of the alkali and alkaline earth metals or complex compoundscontaining hydrogen peroxide. Also, peroxide salts of the alkali oralkaline earth metals are known to be useful in whitening teeth.

Of the many peroxides available to the formulator of tooth whiteningcompositions, hydrogen peroxide (and its adducts or associationcomplexes, such as carbamide peroxide and sodium percarbonate) has beenused almost exclusively. The chemistry of hydrogen peroxide is wellknown, although the specific nature of its interactions with toothchromogens is poorly understood. It is believed that hydrogen peroxidedestroys tooth chromogens by oxidizing unsaturated carbon-carbon,carbon-oxygen, and carbon-nitrogen bonds found in the stain molecules,thus rendering them colorless or soluble.

A related class of compound, the peroxyacids, has been used in laundrydetergents to effectively whiten clothes, due primarily to theirstability in solution and their specific binding abilities to certaintypes of stain molecules. A number of stable, solid peroxyacids havebeen used, including diperoxydodecanoic acid and the magnesium salt ofmonoperoxyphthalic acid. Other peroxyacids, such as peroxyacetic acid,are available as solutions containing an equilibrium distribution ofacetic acid, hydrogen peroxide, peroxyacetic acid and water.Alternatively, a peroxide donor such as sodium perborate or sodiumpercarbonate is formulated together with a peroxyacid precursor. Uponcontact with water, the peroxide donor releases hydrogen peroxide whichthen reacts with the peroxyacid precursor to form the actual peroxyacid.Examples of peroxyacids created in situ include peroxyacetic acid (fromhydrogen peroxide and tetraacetylethylenediamine) and peroxynonanoicacid (from hydrogen peroxide and nonanoyloxybenzene sulfonate).

Peroxyacids have also been used in oral care compositions to whitenstained teeth. U.S. Pat. No. 5,279,816 to Church et al. describes amethod of whitening teeth comprising the application of a peroxyaceticacid-containing composition having an acid pH. EP 545,594 A1 to Churchet al. describes the use of peroxyacetic acid in preparing a compositionfor whitening teeth. The peroxyacetic acid may be present in thecomposition, or alternatively, may be generated in situ by combining aperoxide source with a peroxyacetic acid precursor during use. Forexample, U.S. Pat. No. 5,302,375 to Viscio describes a composition thatgenerates peroxyacetic acid within a vehicle in situ by combining water,acetylsalicylic acid and a water-soluble alkali metal percarbonate.

The most commonly used dental whitening agent is carbamide peroxide(CO(NH₂)₂H₂O₂), also called urea hydrogen peroxide, hydrogen peroxidecarbamide, and perhydrol-urea. Carbamide peroxide had been used bydental clinicians for several decades as an oral antiseptic, and toothbleaching was an observed side effect of extended contact time.Over-the-counter compositions of 10% carbamide peroxide are available asGLY-OXIDE® by Marion Laboratories and PROXIGEL® by Reed and Carnrick,which are low-viscosity compositions that must be held in a tray orsimilar container in order to provide contact with the teeth. Ableaching gel which is able to hold a comfortable-fitting dental tray inposition for an extended time period is available under the trademarkOPALESCENCE® from Ultradent Products, Inc. in South Jordan, Utah.

In order for such compositions to stay in place, the compositions mustbe a viscous liquid or a gel. The use of dental trays also requires thatthe tray be adapted for comfort and fit so that the tray will not exertpressure or cause irritation to the person's teeth or gums. Suchwhitening compositions necessarily should be formulated so as to besufficiently sticky and viscous to resist dilution by saliva.

In one method of whitening an individual's teeth, a dental professionalwill construct a custom made dental bleaching tray for the patient froman impression made of the patient's dentition and prescribe the use ofan oxidizing gel to be dispensed into the bleaching tray and wornintermittently for a period of from about 2 weeks to about 6 months,depending upon the severity of tooth staining. These oxidizingcompositions, usually packaged in small plastic syringes or tubes, aredispensed directly by the patient into the custom-made tooth-bleachingtray, held in place in the mouth for contact times of greater than about60 minutes, and sometimes as long as 8 to 12 hours. The slow rate ofbleaching is in large part the consequence of the very nature offormulations that are developed to maintain stability of the oxidizingcomposition.

For example, U.S. Pat. No. 6,368,576 to Jensen describes tooth whiteningcompositions that are preferably used with a tray so that thecomposition is held in position adjacent to the person's tooth surfacesto be treated. These compositions are described as a sticky matrixmaterial formed by combining a sufficient quantity of a tackifyingagent, such as carboxypolymethylene, with a solvent, such as glycerin,polyethylene glycol, or water.

In another example, U.S. Pat. No. 5,718,886 to Pellico describes a toothwhitening composition in the form of a gel composition containingcarbamide peroxide dispersed in an anhydrous gelatinous carrier, whichincludes a polyol, a thickener, and xanthan gum.

Yet another example is described in U.S. Pat. No. 6,419,905 toHernandez, which describes the use of compositions containing carbamideperoxide (0.3-60%), xylitol (0.5-50%), a potassium salt (0.001-10%) anda fluorine salt (0.15-3%), formulated into a gel that contains between0.5 and 6% by weight of an appropriate gelling agent.

A tooth whitening composition that adheres to the teeth is described inU.S. Pat. Nos. 5,989,569 and 6,045,811 to Dirksing. According to thesepatents, the gel contains 30-85% glycerin or polyethylene glycol, 10-22%urea/hydrogen peroxide complex, 0-12% carboxypolymethylene, 0-1% sodiumhydroxide, 0-100% triethanolamine (TEA), 0-40% water, 0-1% flavor, 0-15%sodium citrate, and 0-5% ethylenediaminetetraacetic acid. The preferredgel according to Dirksing has a viscosity between 200 and 1,000,000 cpsat low shear rates (less than one 1/seconds), and is sufficientlyadhesive so as to obviate the need for a tray.

Currently available tooth-bleaching compositions have a significantdisadvantage in that they cause tooth sensitization in over 50% ofpatients. Tooth sensitivity may result from the movement of fluidthrough the dentinal tubules, which is sensed by nerve endings in thetooth, due to the presence of glycerin, propylene glycol andpolyethylene glycol in these compositions. This can result in varyingamounts of tooth sensitivity following exposure of the teeth to heat,cold, overly sweet substances, and other causative agents.

Prolonged exposure of teeth to bleaching compositions, as practiced atpresent, has a number of adverse effects in addition to that of toothsensitivity. These adverse effects include leaching of calcium from theenamel layer at a pH less than 5.5; penetration of the intact enamel anddentin by the bleaching agents and risking damage to pulpal tissue; anddilution of the bleaching compositions with saliva resulting in leachingfrom the dental tray and subsequent ingestion by the user.

Some oxidizing compositions (generally having relatively highconcentrations of oxidizers) are applied directly to the tooth surfaceof a patient in a dental office setting under the supervision of adentist or dental hygienist. Theoretically, such tooth whiteningstrategies yield faster results and better overall patient satisfaction.However, due to the high concentration of oxidizing agents contained inthese so called “in-office” compositions, they can be hazardous to thepatient and practitioner alike if not handled with care. The patient'ssoft tissues (the gingiva, lips, and other mucosal surfaces) must firstbe isolated from potential exposure to the active oxidizing agent by theuse of a perforated rubber sheet (known as a rubber dam), so that onlythe teeth protrude. Alternatively, the soft tissue may be isolated fromthe oxidizers to be used in the whitening process by covering the softtissue with a polymerizable composition that is shaped to conform to thegingival contours and subsequently cured by exposure to a high intensitylight source. Once the soft tissue has been isolated and protected, thepractitioner may apply the oxidizing agent directly onto the stainedtooth surfaces for a specified period of time or until a sufficientchange in tooth color has occurred. Typical results obtained through theuse of an in-office tooth whitener, range from about 2 to 3 shades (asmeasured with the VITA Shade Guide, VITA Zahnfarbik).

The range of tooth shades in the VITA Shade Guide varies from very light(B1) to very dark (C4). A total of 16 tooth shades constitute the entirerange of colors between these two endpoints on a scale of brightness.Patient satisfaction with a tooth whitening procedure increases with thenumber of tooth shade changes achieved, with a generally acceptedminimum change desirable of about 4 to 5 VITA shades.

It is desirable, with respect to dental care products for toothwhitening, to provide dental care products utilizing an adhesivehydrogel that includes a whitening agent for removing stains from anindividual's teeth. In addition, there is a constant need for thedevelopment of products to provide a protective dressing or protectantfor skin and mucosal surfaces or to provide delivery of active agents,for example transdermal and transmucosal delivery of agents to skin,mucosal tissue, tooth surface, gums, mucous membranes and other oraltissue. Compositions are desired that do not require the use of dentaltrays to provide contact between the active agent and the teeth or otheroral surface. Such products ideally would cause minimal or no toothsensitivity, would minimize or eliminate leakage of the active agentresulting in ingestion by the user or resulting in damage or irritationto the gums or mucous membranes of the mouth, would provide for longerwear duration, sustained dissolution of the active agent, improvedefficacy, and be well tolerated by patients. It would also be desirableto provide a dental care product that is a solid composition andself-adhesive but which does not stick to the fingers of the user, orthat is a non-solid (e.g., liquid or gel) and which forms a film whendry. The instant invention addresses these needs.

SUMMARY OF THE INVENTION

One aspect of the invention relates to a composition comprising: awater-swellable, water-insoluble polymer or a water-soluble polymer; anda blend of a hydrophilic polymer and a complementary oligomer capable ofhydrogen bonding or electrostatic bonding to the hydrophilic polymer. Anactive agent such as a tooth whitening agent may also be included. Inone embodiment, the composition further comprises a secondwater-swellable, water-insoluble polymer that has different pHsolubility characteristics that than the first water-swellable,water-insoluble polymer or water-soluble polymer.

Another aspect of the invention pertains to a phase separating,film-forming composition comprising: a first water-swellable polymerthat is insoluble in water at a pH less than about 5.5 or awater-soluble polymer; a blend of a hydrophilic polymer and acomplementary oligomer capable of hydrogen bonding to the hydrophilicpolymer; a second water-swellable polymer that is insoluble in water atall pH values; and an optional active agent. The composition undergoesphase separation once in use, forming a plurality of film layers.

In a preferred embodiment, the first water-swellable, water-insolublepolymer is an acrylate-based polymer or copolymer; the hydrophilicpolymer is an poly(N-vinyl lactam), poly(N-vinyl amide),poly(N-alkylacrylamide), or copolymer and blend thereof; thecomplementary oligomer capable of hydrogen bonding to the hydrophilicpolymer is a polyalkylene glycol or a carboxyl-terminated polyalkyleneglycol; and the second water-swellable, water-insoluble polymer is acellulose ester, or an acrylate-based polymer or copolymer. A preferredactive agent is a whitening agent such as a peroxide.

The composition optionally comprises a low molecular weight plasticizer,and may also comprise at least one additive selected from the groupconsisting of flavorants, sweeteners, fillers, preservatives, pHregulators, softeners, thickeners, colorants (e.g., pigments, dyes,refractive particles, etc.), flavorants (e.g., sweeteners, flavors),stabilizers, surfactants, toughening agents and detackifiers.

In a preferred method of using the composition, the composition is atooth whitening composition and is applied to the teeth in need ofwhitening, and then removed when the degree of whitening has beenachieved. In certain embodiments, the tooth whitening composition istranslucent, and the composition is removed when the user is satisfiedwith the degree of whitening achieved.

Yet another aspect of the invention pertains to a composition comprisinga first water-swellable, water-insoluble polymer or a water-solublepolymer; a second water-swellable, water-insoluble polymer; a blend of ahydrophilic polymer and a complementary oligomer capable of hydrogenbonding to the hydrophilic polymer; and an agent selected from the groupconsisting of peroxides, metal chlorites, perborates, percarbonates,peroxyacids, and combinations thereof.

Another aspect of the invention relates to a method for preparing ahydrogel film suitable for incorporation into an oral care, transmucosalor transdermal composition or system is provided. This method comprisespreparing a solution or a gel of a first water-swellable,water-insoluble polymer or a water-soluble polymer; a secondwater-swellable, water-insoluble polymer; a hydrophilic polymer; and acomplementary oligomer capable of hydrogen bonding or electrostaticbonding to the hydrophilic polymer, in a solvent; depositing a layer ofthe solution on a substrate to provide a coating thereon; and heatingthe coated substrate to a temperature in the range of about 80° C. toabout 100° C. for a time period in the range of about 1 to about 4hours, thereby providing a hydrogel film on the substrate.

In another method of forming a composition of the invention, the methodcomprises melt processing through an extruder a mixture of a firstwater-swellable, water-insoluble polymer or a water-soluble polymer; asecond water-swellable, water-insoluble polymer; a hydrophilic polymer;and a complementary oligomer capable of hydrogen bonding orelectrostatic bonding to the hydrophilic polymer, to form an extrudedcomposition; wherein the composition is extruded as a film of desiredthickness onto a suitable substrate.

The method further comprises loading the hydrogel film with an activeagent such as a whitening agent, thereby providing a tooth whiteningcomposition.

The adhesive compositions of the invention provide a number ofsignificant advantages relative to the prior art. In particular, thepresent compositions:

-   -   (1) provide ease of handling;    -   (2) are readily modified during manufacture so that properties        such as adhesion, absorption, translucence, and swelling can be        controlled and optimized;    -   (3) can be formulated so that tack increases or decreases in the        presence of moisture so that the composition is not sticky until        moistened;    -   (4) minimize leakage of the active agent, when included, from        the composition onto a skin surface or a mucosal surface (e.g.,        into the user's mouth);    -   (5) can be fabricated in translucent from, enabling the user to        view the extent of whitening without removing the hydrogel        composition from the teeth or skin/mucosal surface;    -   (6) minimize damage to gums or mucous membranes in the mouth;    -   (7) can be worn comfortably and unobtrusively;    -   (8) are easily removed from the teeth or skin/mucosal surface,        and leave no residue;    -   (9) are amenable to extended duration of wear or action; and    -   (10) can provide sustained and controlled release of a variety        of active agents.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions and Nomenclature

Before describing the present invention in detail, it is to beunderstood that unless otherwise indicated this invention is not limitedto specific hydrogel materials or manufacturing processes, as such mayvary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only, and is notintended to be limiting. It must be noted that, as used in thisspecification and the appended claims, the singular forms “a,” “an,” and“the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a hydrophilic polymer”includes not only a single hydrophilic polymer but also a combination ormixture of two or more different hydrophilic polymers, reference to “aplasticizer” includes a combination or mixture of two or more differentplasticizers as well as a single plasticizer, and the like.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

The definitions of “hydrophobic” and “hydrophilic” polymers are based onthe amount of water vapor absorbed by polymers at 100% relativehumidity. According to this classification, hydrophobic polymers absorbonly up to 1 wt % water at 100% relative humidity (“rh”), whilemoderately hydrophilic polymers absorb 1-10% wt % water, hydrophilicpolymers are capable of absorbing more than 10 wt % of water, andhygroscopic polymers absorb more than 20 wt % of water. A“water-swellable” polymer is one that absorbs an amount of water greaterthan at least 25 wt % of its own weight, and preferably at least 50 wt %of its own weight, upon immersion in an aqueous medium.

The term “crosslinked” herein refers to a composition containingintramolecular and/or intermolecular crosslinks, whether arising throughcovalent or noncovalent bonding. “Noncovalent” bonding includes bothhydrogen bonding and electrostatic (ionic) bonding.

The term “polymer” includes linear and branched polymer structures, andalso encompasses crosslinked polymers as well as copolymers (which mayor may not be crosslinked), thus including block copolymers, alternatingcopolymers, random copolymers, and the like. Those compounds referred toherein as “oligomers” are polymers having a molecular weight below about1000 Da, preferably below about 800 Da.

The term “hydrogel” is used in the conventional sense to refer towater-swellable polymeric matrices that can absorb a substantial amountof water to form elastic gels, wherein “matrices” are three-dimensionalnetworks of macromolecules held together by covalent or noncovalentcrosslinks. Upon placement in an aqueous environment, dry hydrogelsswell to the extent allowed by the degree of cross-linking.

“Phase” is traditionally defined as a homogeneous part of aheterogeneous system. Respectively, “phase separation” is thetransformation of a homogeneous system to heterogeneous one.Conventionally, the process of phase separation is accompanied with theformation of an interphase border between the phases of differentcomposition. Typical examples of phase separation include sol-geltransition, precipitation in solution, or the spontaneous formation of amulti-layer (laminate) structure.

The terms “active agent,” “pharmacologically active agent” and “drug”are used interchangeably herein to refer to a chemical material orcompound that induces a desired pharmacological, physiological effect,and include agents that are therapeutically effective, prophylacticallyeffective, or cosmeceutically effective. The ter ins also encompasspharmaceutically acceptable, pharmacologically active derivatives andanalogs of those active agents specifically mentioned herein, including,but not limited to, salts, esters, amides, prodrugs, active metabolites,inclusion complexes, analogs, and the like. When the terms “activeagent,” “pharmacologically active agent” and “drug” are used, it is tobe understood that both the active agent per se as well aspharmaceutically acceptable, pharmacologically active salts, esters,amides, prodrugs, active metabolites, inclusion complexes, analogs,etc., are included.

The term “tooth whitening composition” refers to a composition thatcontains a hydrogel, as defined herein, and a whitening agent.

The term “whitening agent” typically refers to an oxidizing agent suchas a peroxide or a chlorite, as will be discussed in greater detailbelow. In some instances, the whitening agent may be an enzyme or othercatalytic means for removing a stain from the teeth. The whitening agentmay include one or more additional whitening agents, surfactants,antiplaque agents, antitartar agents and abrasive agents. The whiteningagent may have additional therapeutic benefits.

The term “effective amount” or “a cosmeceutically effective amount” of acosmeceutically active agent is meant a nontoxic but sufficient amountof a cosmeceutically active agent to provide the desired cosmeticeffect. The term “effective amount” or “a therapeutically effectiveamount” of a drug or pharmacologically active agent is intended to meana nontoxic but sufficient amount of the drug or agent to provide thedesired therapeutic effect. The amount that is “effective” will varyfrom subject to subject, depending on the age and general condition ofthe individual, the particular active agent or agents, and the like.Thus, it is not always possible to specify an exact “effective amount.”However, an appropriate “effective” amount in any individual case may bedetermined by one of ordinary skill in the art using routineexperimentation. Furthermore, the exact “effective” amount of an activeagent incorporated into a composition or dosage form of the invention isnot critical, so long as the concentration is within a range sufficientto permit ready application of the formulation so as to deliver anamount of the active agent that is within a therapeutically effectiverange.

The term “surface” as in “oral cavity” surface or “body surface” isintended to include body surfaces such as skin, nails and mucosal tissue(e.g., sublingual, buccal, vaginal, rectal, urethral), as well assurfaces in and around the oral cavity (e.g., teeth, lips, gums, mucousmembranes), as well as the surface of various skin wounds.

“Transdermal” and “transmucosal” drug delivery is meant administrationof a drug to the skin or mucosal tissue surface of an individual so thatthe drug passes through the skin or mucosal tissue and into theindividual's blood stream, thereby providing a systemic effect. The term“transmucosal” is intended to include administration of a drug to themucosal (e.g., sublingual, buccal, vaginal, rectal, urethral) surface ofan individual so that the drug passes through the mucosal tissue andinto the individual's blood stream. The terms “transdermal” and“transmucosal” are intended to cover both local and systemic effects,and therefore includes topical administration, i.e., delivery of atopical agent to the skin or mucosa, as in, for example, the treatmentof various skin and mucosal disorders to provide a local effect.

The terms “tack” and “tacky” are qualitative. However, the terms“substantially nontacky” “slightly tacky” and “tacky,” as used herein,may be quantified using the values obtained in a PKI or TRBT tackdetermination method, as follows. By “substantially nontacky” is meant ahydrogel composition that has a tack value that is less than about 25g-cm/sec, by “slightly tacky” is meant a hydrogel composition that has atack value in the range of about 25 g-cm/sec to about 100 g-cm/sec, andby “tack” is meant a hydrogel composition that has a tack value of atleast 100 g-cm/sec.

The term “water-insoluble” refers to a compound or composition whosesolubility in water is less than 5 wt %, preferably less than 3 wt %,more preferably less than 1 wt % (measured in water at 20° C.).Similarly, the term “water-soluble” refers to a compound or compositionwhose solubility in water is greater than 5 wt %, preferably greaterthan 3 wt %, more preferably greater than 1 wt % (measured in water at20° C.).

The term “translucent” is used herein to signify a material capable oftransmitting light so that objects or images can be seen through thematerial. Translucent materials herein may or may not be “transparent,”meaning that the material is optically clear. The term “translucent”indicates that a material is not “opaque,” in which case objects andimages cannot be seen through the material.

II. Compositions

The composition of the invention is comprised of a water-swellable,water-insoluble polymer or a water-soluble polymer, a blend of ahydrophilic polymer and a complementary oligomer capable of hydrogenbonding to the hydrophilic polymer, and an optional active agent such asa whitening agent. The composition also includes a secondwater-swellable, water insoluble polymer. In certain embodiments one orboth of the water swellable, water-insoluble polymers are also capableof H-bonding with the hydrophilic polymer. Similarly, in certainembodiments one or both of the water-soluble polymer and the waterswellable, water-insoluble polymer are also capable of H-bonding withthe hydrophilic polymer.

In one embodiment of a non-solid composition of the invention, the firstwater-swellable, water-insoluble polymers (or the water-soluble polymer)and the second water-swellable, water-insoluble polymer represents about0.1-20 wt %, preferably about 4-15 wt % of the composition; and thehydrophilic polymer represents about 1-30 wt %, preferably about 5-25 wt% of the composition. In another embodiment of a non-solid compositionof the invention, the first water-swellable, water-insoluble polymers(or the water-soluble polymer) and the second water-swellable,water-insoluble polymer represents about 1-30 wt %, preferably about5-25 wt % of the composition; and the hydrophilic polymer representsabout 0.1-20 wt %, preferably about 4-15 wt % of the composition. Theactive agent, when present, can represent about 0.1-60 wt %, preferablyabout 1-40 wt % of the non-solid composition. The complementary oligomercan represent about 0.1-20 wt %, preferably about 0.5-10 wt % of thenon-solid composition. Optimally, the complementary oligomer representsabout 1-85 wt %, preferably about 5-50 wt % of the hydrophilicpolymer/complementary oligomer blend in a non-solid composition.

In one embodiment of a solid composition of the invention, the firstwater-swellable polymer (or water-soluble polymer) and the secondwater-swellable water-insoluble polymer represents about 1-20 wt %,preferably about 6-12 wt % of the composition; and the hydrophilicpolymer represents about 20-80 wt %, preferably about 40-60 wt % of thecomposition. In another embodiment of a solid composition of theinvention, the first water-swellable polymer (or water-soluble polymer)and the second water-swellable water-insoluble polymer represents about20-80 wt %, preferably about 40-60 wt % of the composition; and thehydrophilic polymer represents about 1-20 wt %, preferably about 6-12 wt% of the composition. The active agent, when present, can representabout 0.1-60 wt %, preferably about 1-30 wt % of the solid composition.The complementary oligomer can represent about 10-50 wt %, preferablyabout 15-35 wt % of the solid composition. Optimally, the complementaryoligomer represents about 10-80 wt %, preferably about 20-50 wt % of thehydrophilic polymer/complementary oligomer blend in a solid composition.

In one embodiment, the composition is a tooth whitening composition,where the whitening agent functions to whiten the tooth surface to whichthe composition is applied. However, the whitening agent may have otherutilities, for example as a therapeutic agent or other type ofcosmeceutical agent, e.g., for skin lightening. Therefore, thecompositions described herein may find utility as pharmaceuticalcompositions to be applied to a body surface (e.g., teeth, nails, skin,mucosa, etc.) for the treatment of a disease state. For example,hydrogen peroxide also has antiseptic and anti-acne properties, as wellas being a whitening agent. Therefore, the invention also contemplatestreating an infection or acne by applying a hydrogen peroxide-containingcomposition of the invention to a body surface. Other diseases statesinclude, by way of illustration and not limitation, fungal infections,acne, wounds, skin lightening, and so forth. In addition, a number ofactive agents can be incorporated in the composition of the invention totreat a variety of diseases that affect the oral cavity.

A. Water-Swellable, Water-Insoluble Polymers and Water-Soluble Polymers

The first water-swellable, water-insoluble polymer is part of the bodysurface-contacting composition and serves to, for example, provideadhesive properties or regulate swelling and dissolution properties. Thesecond water-swellable, water-insoluble polymer serves to provide aprotective film layer over the body surface-contacting layer.

The first and second water-swellable, water-insoluble polymers can befrom the same general class of polymers, but will each be selected so asto have different solubility characteristics in aqueous media. The firstpolymer is selected so as to be insoluble in aqueous media, e.g., water,within a selected pH range, typically less than about pH 5.5, i.e., thefirst polymer has pH-dependent solubility. The first polymer willgenerally dissolve in aqueous media at a pH greater than 5.5. The secondpolymer is selected so as to be insoluble in aqueous media at all pHvalues, i.e., the second polymer has pH-independent insolubility. Inthis manner, when the composition is added to an aqueous environmentsuch as the 6-8 pH typically found in the oral cavity, phase separationoccurs between the first polymer (which is soluble at a high pH) and thesecond polymer. This results in the second water-swellable,water-insoluble polymer forming a film over the firstpolymer/hydrophilic polymer/complementary oligomer film.

The outer film formed by the second polymer is insoluble in aqueousmedia but remains water-permeable. Over time, the underlying film layerdissolves and the outer film can either be removed of if left forsufficient period of time breaks up into minute particles that graduallyget washed away, e.g., by saliva. Removal of both the underlying filmand the outer film can also be facilitated by gentle rubbing with theuser's finger or a toothbrush.

The weight ratio of the first to the second water-swellable,water-insoluble polymer can be within the range of about 1:3 to 3:1. Ina preferred embodiment the ratio is within the range of about 1.5:1 to2:1.

The first and second water-swellable, water-insoluble polymers arepolymers that are capable of swelling when immersed in an aqueousliquid. The polymers generally swell by at least 25 wt %, and preferablyby at least 50 wt % of its own weight when immersed in water or aqueoussolution. In some embodiments utilizing certain hydrophilic polymers,the composition may swell by as much as 1400 wt % of its dry weight.

1. First Water-Swellable, Water-Insoluble Polymer

The adhesion profile can also be tailored based on type of polymerselected as the first polymer, the composition ratio and the extent ofwater in the blend. The first water-swellable, water-insoluble polymeris selected so as to provide the desired adhesion profile with respectto hydration. That is, a composition is provided that is generallysubstantially nontacky prior to contact with water, but becomes tackyupon contact with a moist surface.

The first water-swellable, water-insoluble polymer is capable of atleast some degree of swelling when immersed in an aqueous liquid but isinsoluble in water at pH values less than about 5.5, while being solubleat higher pH values, such as those encountered in the mouth.

The first water-swellable, water-insoluble polymer can be anacrylate-based polymer or copolymer, i.e., an acrylic acid or acrylicacid ester polymer or copolymer (an “acrylate” polymer).

Acrylate polymers are particularly suited for use as the firstwater-swellable polymers, and are generally formed from acrylic acid,methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate,ethyl methacrylate, and/or other vinyl monomers. Suitable acrylatepolymers are those copolymers available under the tradename “Eudragit”from Rohm Pharma (Germany). The Eudragit® series E, L, S, RL, RS and NEcopolymers are available solubilized in organic solvent, in an aqueousdispersion, or as a dry powder. Preferred acrylate polymers arecopolymers of methacrylic acid and methyl methacrylate, such as theEudragit L and Eudragit S series polymers. Particularly preferred suchcopolymers are Eudragit L 30D-55 and Eudragit L 100-55 (their chemicalname is poly(methacrylic acid-co-ethyl acrylate 1:1; the lattercopolymer is a spray-dried form of Eudragit L 30D-55 that can bereconstituted with water). The molecular weight of the Eudragit L 30D-55and Eudragit L 100-55 copolymers is approximately 135,000 Da, with aratio of free carboxyl groups to ester groups of approximately 1:1. TheEudragit L 100-55 copolymer is generally insoluble in aqueous fluidshaving a pH below 5.5, and is therefore particularly well suited for useas the first water-swellable polymer. Another particularly suitablemethacrylic acid-methyl methacrylate copolymer is Eudragit S-100, whichdiffers from Eudragit L 30D-55 in that the ratio of free carboxyl groupsto ester groups is approximately 1:2. Eudragit S-100 is insoluble at pHbelow 5.5, but unlike Eudragit L 30D-55, is poorly soluble in aqueousfluids having a pH in the range of 5.5 to 7.0. This copolymer is solubleat pH 7.0 and above. Eudragit L 100 may also be used, which has apH-dependent solubility profile between that of Eudragit L 30D-55 andEudragit S-100, insofar as it is insoluble at a pH below 6.0. It will beappreciated by those skilled in the art that Eudragit L 30D-55, L100-55, L 100, and S 100 can be replaced with other acceptable polymershaving similar pH-dependent solubility characteristics.

Other suitable acrylate polymers are those methacrylic acid/ethylacrylate copolymers available under the tradename “Kollicoat” from BASFAG (Germany). For example, Kollicoat MAE has the same molecularstructure as Eudragit L 100-55.

When the first water-swellable polymer is an acrylic acid or acrylatepolymer, a hydrogel is provided that can be reversibly dried, i.e.,after removal of water and any other solvents, the dried hydrogel may bereconstituted to its original state by addition of water. In addition,hydrophilic hydrogels prepared with an acrylic acid/acrylatewater-swellable polymer are generally substantially nontacky prior tocontact with water, but become tacky upon contact with a moist surface,such as is found in the interior of the mouth, such as on the surface ofthe teeth, This property of being nontacky prior to contact with waterenables positioning or repositioning on a chosen surface before, or asthe hydrogel becomes tacky. Once hydrated, the hydrogel becomes tackyand adheres to the surface of the teeth or skin/mucosal surface.

In addition, acrylate-containing compositions can generally provideswelling in the range of about 400% to 1500% upon immersion of thehydrogel composition in water or other aqueous liquid, at a pH of lessthan 5.5, although the ratio of the acrylate polymer to the hydrophilicpolymer/complementary oligomer blend can be selected such that the rateand extent of swelling in an aqueous environment has a predeterminedpH-dependence. This feature also provides for retroactive incorporationof whitening agents or other active agents, such as loading thecomposition with peroxide, peroxy acids, chlorites, stabilizers,flavoring agents, etc.

By contrast, incorporating a cellulose ester as one of thewater-swellable polymers renders the hydrogel tacky prior to applicationto a moist surface, but nontacky upon absorption of water. It will beappreciated that such a composition may be desirable when a decrease intack is desired for ultimate removal of the product from the teeth.

2. Water-Soluble Polymers

Suitable water-soluble polymers include, by way of illustration and notlimitation, water-soluble cellulose derived polymers; polyvinyl alcohol;collagen; and naturally occurring polysaccharides.

Exemplary water-soluble cellulose derived polymers includehydroxypropylcellulose, hydroxyethylcellulose, methylcellulose,hydroxypropyl methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, hydratecellulose (cellophane), andhydroxypropylmethylcellulose.

Exemplary naturally occurring polysaccharides include agars of variousorigin such as gum agar; alginates such as alginic acid, salts ofalginic acid (e.g., calcium alginate, potassium alginate, sodiumalginate), and derivatives of alginic acid (e.g. propylene glycolalginate, Kelcoloid®, Monsanto); carrageenans including kappa-, iota-and lambda carrageenans; chitin; chitosan; glucomannan; gellan gum(Kelcogel®, Monsanto); gelatin; gum guar (TIC Gums); gum arabic; gumghatti; gum karaya; gum tragacanth; locust bean gum; pectins such aspectin and amylopectin; pullulan; starches and starch derivatives suchas potato starch acetate, Clearam® CH10, Roquette; tamarind gum;xanthans such as xanthane gum; and combinations thereof.

3. Second Water-Swellable, Water-Insoluble Polymer

The second water-swellable, water-insoluble polymer is capable of atleast some degree of swelling when immersed in an aqueous liquid but isinsoluble in water at all pH values.

The second water-swellable, water-insoluble polymer can be a cellulosicpolymer, a cellulose ester, or an acrylate-based polymer or copolymer,i.e., an acrylic acid or acrylic acid ester polymer or copolymer (an“acrylate” polymer). The second polymer may also provide some desiredadhesion prior to phase separation. For example, when the second polymeris a cellulose ester, the composition is generally tacky prior tocontact with water (e.g., with a moist surface) but gradually loses tackas the composition absorbs moisture. When the second polymer is anacrylate polymer or copolymer, a composition is provided that isgenerally substantially nontacky prior to contact with water, butbecomes tacky upon contact with a moist surface.

Exemplary cellulose esters include, for example, cellulose acetate,cellulose acetate propionate (CAP), cellulose acetate butyrate (CAB),cellulose acetate phthalate, cellulose propionate (CP), cellulosebutyrate (CB), cellulose propionate butyrate (CPB), cellulose diacetate(CDA), cellulose triacetate (CTA), or the like. These cellulose estersare described in U.S. Pat. Nos. 1,698,049, 1,683,347, 1,880,808,1,880,560, 1,984,147, 2,129,052, and 3,617,201, and may be preparedusing techniques known in the art or obtained commercially. Commerciallyavailable cellulose esters suitable herein include CA 320, CA 398, CAB381, CAB 551, CAB 553, CAP 482, CAP 504, all available from EastmanChemical Company, Kingsport, Term. Such cellulose esters typically havea number average molecular weight of between about 10,000 and about75,000.

Generally, the cellulose ester comprises a mixture of cellulose andcellulose ester monomer units; for example, commercially availablecellulose acetate butyrate contains cellulose acetate monomer units aswell as cellulose butyrate monomer units and unesterified cellulosemonomer units, while cellulose acetate proprionate contains monomerunits such as cellulose proprionate. Preferred cellulose esters hereinare cellulose acetate propionate compositions and cellulose acetatebutyrate compositions having the butyryl, propionyl, acetyl, andunesterified (OH) cellulose content as indicated below:

Acetyl OH MW T_(g) T_(m) (%) (%) (g/mole) (° C.) (° C.) CelluloseAcetate Butyrate 17-52% 2.0-29.5 1.1-4.8 12,000-70,000  96-141 130-240Butyrate Cellulose Acetate Propionate 42.5-47.7% 0.6-1.5  1.7-5.015,000-75,000 142-159 188-210 PropionateThe preferred molecular weight, glass transition temperature (T_(g)) andmelting temperature (T_(m)) are also indicated. Also, suitablecellulosic polymers typically have an inherent viscosity (I.V.) of about0.2 to about 3.0 deciliters/gram, preferably about 1 to about 1.6deciliters/gram, as measured at a temperature of 25° C. for a 0.5 gramsample in 100 ml of a 60/40 by weight solution ofphenol/tetrachloroethane. When prepared using a solvent castingtechnique, the water-swellable, water-insoluble polymer should beselected to provide greater cohesive strength and thus facilitate filmforming (generally, for example, cellulose acetate propionate tends toimprove cohesive strength to a greater degree than cellulose acetatebutyrate).

Exemplary cellulosics include, for example, methyl cellulose and ethylcellulose.

Acrylate polymers are also particularly suited for use as the secondwater-swellable polymers, and are described above as the Eudragit® andKollicoat® polymers. For use as the second water-swellable polymer,however, the acrylate polymers are selected so as to have pH-independentsolubility. There are numerous pH-independent polymers in the Eudragit®RL and Eudragit RS series, including RL 30D, RL PO, RL 100, RS 30D, RSPO, and RS 100. The Eudragit RL 100 (poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2)and RS 100 (poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1)copolymers are particularly well suited for use as the secondwater-swellable polymer; both are copolymers of ethyl acrylate, methylmethacrylate and possess a low content of methacrylic acid ester withquaternary ammonium groups present as chloride salts.

B. Hydrophilic Polymers

The second component of the hydrogel composition is a blend of ahydrophilic polymer and a complementary oligomer capable of hydrogenbonding to the hydrophilic polymer, and optionally capable of conicallyor covalently bonding to the hydrophilic polymer as well. Thehydrophilic polymer is generally a relatively high molecular weightpolymer, and the complementary oligomer is generally a lower molecularweight polymer.

Suitable hydrophilic polymers include repeating units derived from anN-vinyl lactam monomer, a carboxy vinyl monomer, a vinyl ester monomer,an ester of a carboxy vinyl monomer, a vinyl amide monomer, and/or ahydroxy vinyl monomer. Such polymers include, by way of example,poly(N-vinyl lactams), poly(N-vinyl acrylamides),poly(N-alkylacrylamides), substituted and unsubstituted acrylic andmethacrylic acid polymers (e.g., polyacrylic acids and polymethacrylicacids), polyvinyl alcohol (PVA), polyvinylamine, copolymers thereof andcopolymers with other types of hydrophilic monomers (e.g. vinylacetate).

Poly(N-vinyl lactams) useful herein are preferably noncrosslinkedhomopolymers or copolymers of N-vinyl lactam monomer units, with N-vinyllactam monomer units representing the majority of the total monomericunits of a poly(N-vinyl lactams) copolymer. Preferred poly(N-vinyllactams) for use in conjunction with the invention are prepared bypolymerization of one or more of the following N-vinyl lactam monomers:N-vinyl-2-pyrrolidone; N-vinyl-2-valerolactam; andN-vinyl-2-caprolactam. Nonlimiting examples of non-N-vinyl lactamcomonomers useful with N-vinyl lactam monomeric units includeN,N-dimethylacrylamide, acrylic acid, methacrylic acid,hydroxyethylmethacrylate, acrylamide, 2-acrylamido-2-methyl-1-propanesulfonic acid or its salt, and vinyl acetate.

Poly(N-alkylacrylamides) include, by way of example,poly(methacrylamide) and poly(N-isopropyl acrylamide) (PNIPAM).

Polymers of carboxy vinyl monomers are typically formed from acrylicacid, methacrylic acid, crotonic acid, isocrotonic acid, itaconic acidand anhydride, a 1,2-dicarboxylic acid such as maleic acid or fumaricacid, maleic anhydride, or mixtures thereof, with preferred hydrophilicpolymers within this class including polyacrylic acid andpolymethacrylic acid, with polyacrylic acid most preferred.

Preferred hydrophilic polymers herein are the following: poly(N-vinyllactams), particularly polyvinyl pyrrolidone (PVP) and polyvinylcaprolactam (PVCap); poly(N-vinyl acetamides), particularlypolyacetamide per se; polymers of carboxy vinyl monomers, particularlypolyacrylic acid and polymethacrylic acid; and copolymers and blendsthereof. PVP and PVCap are particularly preferred.

The molecular weight of the hydrophilic polymer is not critical;however, the number average molecular weight of the hydrophilic polymeris generally in the range of approximately 100,000 to 2,000,000, moretypically in the range of approximately 500,000 to 1,500,000. Theoligomer is “complementary” to the hydrophilic polymers in that it iscapable of hydrogen bonding thereto. Preferably, the complementaryoligomer is terminated with hydroxyl groups, amino or carboxyl groups.The oligomer typically has a glass transition temperature T_(g) in therange of about −100° C. to about −30° C. and a melting temperature T_(m)lower than about 20° C. The oligomer may be also amorphous. Thedifference between the T_(g) values of the hydrophilic polymer and theoligomer is preferably greater than about 50° C., more preferablygreater than about 100° C., and most preferably in the range of about150° C. to about 300° C. The hydrophilic polymer and complementaryoligomer should be compatible, i.e. capable of forming a homogeneousblend that exhibits a single T_(g), intermediate between those of theunblended components.

C. Complementary Oligomer

Generally, the complementary oligomer will have a molecular weight inthe range from about 45-800, preferably in the range of about 45-600.The complementary oligomer is preferably a low molecular weightpolyalkylene glycol (molecular weight 300-600) such as polyethyleneglycol 400, which can also serve as a low molecular weight plasticizer.Alternatively, a different compound can be incorporated as an additionallow molecular weight plasticizer, in which case any of the low molecularweight plasticizers described below can be used. In one embodiment ofthe invention, the complementary oligomer is a complementary lowmolecular weight or oligomeric plasticizer that contains at least twofunctional groups per molecule that are capable of hydrogen bonding tothe hydrophilic polymer.

In some instances, the complementary oligomer may also serve as a lowmolecular weight plasticizer. Alternatively, a different compound can beincorporated as an additional low molecular weight plasticizer and, ifincluded, would be present as approximately 30 to 35 wt % of thecomposition.

Examples of suitable complementary oligomers include, but are notlimited to, low molecular weight polyalcohols (e.g. glycerol), monomericand oligoalkylene glycols such as ethylene glycol and propylene glycol,ether alcohols (e.g., glycol ethers), carbonic diacids, alkane diolsfrom butane diol to octane diol, including carboxyl-terminated andamino-terminated derivatives of polyalkylene glycols. Polyalkyleneglycols, optionally carboxyl-terminated, are preferred herein, andpolyethylene glycol having a molecular weight in the range of about300-600 is an optimal complementary oligomer.

It will be appreciated from the foregoing that a single compound, e.g.,a low molecular weight polyalkylene glycol such as polyethylene glycolhaving a molecular weight in the range of about 300-600, can serve asboth the complementary oligomer and the low molecular weightplasticizer.

As discussed in U.S. Patent Publication No. 2002/0037977 to Feldstein etal., the ratio of the hydrophilic polymer to the complementary oligomerin the aforementioned blend affects both adhesive strength and thecohesive strength. As explained in the aforementioned patentapplication, the complementary oligomer decreases the glass transitionof the hydrophilic polymer/complementary oligomer blend to a greaterdegree than predicted by the Fox equation, which is given by thefollowing equation:

$\frac{1}{T_{g\mspace{11mu}{predicted}}} = {\frac{w_{pol}}{T_{g_{pol}}} + \frac{w_{pl}}{T_{g_{pl}}}}$where T_(g predicted) is the predicted glass transition temperature ofthe hydrophilic polymer/complementary oligomer blend, w_(pol) is theweight fraction of the hydrophilic polymer in the blend, w_(pl) is theweight fraction of the complementary oligomer in the blend, T_(g pol) isthe glass transition temperature of the hydrophilic polymer, andT_(g pl) is the glass transition temperature of the complementaryoligomer. As also explained in that patent application, an adhesivecomposition having optimized adhesive and cohesive strength can beprepared from a hydrophilic polymer and a complementary oligomer byselecting the components and their relative amounts to give apredetermined deviation from T_(g predicted). Generally, to maximizeadhesion, the predetermined deviation from T_(g predicted) will be themaximum negative deviation, while to minimize adhesion, any negativedeviation from T_(g predicted) is minimized.

As the complementary oligomer may itself act as a plasticizer, it is notgenerally necessary to incorporate an added plasticizer. However,inclusion of an additional low molecular weight plasticizer in thecomposition is optional and may, in some cases, be advantageous.Suitable low molecular weight plasticizers include: dialkyl phthalates,dicycloalkyl phthalates, diaryl phthalates, and mixed alkyl-arylphthalates, as represented by dimethyl phthalate, diethyl phthalate,dipropyl phthalate, di(2-ethylhexyl)-phthalate, di-isopropyl phthalate,diamyl phthalate and dicapryl phthalate; alkyl and aryl phosphates suchas tributyl phosphate, trioctyl phosphate, tricresyl phosphate, andtriphenyl phosphate; alkyl citrate and citrate esters such as trimethylcitrate, triethyl citrate, tributyl citrate, acetyl triethyl citrate,and trihexyl citrate; dialkyl adipates such as dioctyl adipate (DOA);also referred to as bis(2-ethylhexyl)adipate), diethyl adipate,di(2-methylethyl)adipate, and dihexyl adipate; dialkyl tartrates such asdiethyl tartrate and dibutyl tartrate; dialkyl sebacates such as diethylsebacate, dipropyl sebacate and dinonyl sebacate; dialkyl succinatessuch as diethyl succinate and dibutyl succinate; alkyl glycolates, alkylglycerolates, glycol esters and glycerol esters such as glyceroldiacetate, glycerol triacetate (triacetin), glycerol monolactatediacetate, methyl phthalyl ethyl glycolate, butyl phthalyl butylglycolate, ethylene glycol diacetate, ethylene glycol dibutyrate,triethylene glycol diacetate, triethylene glycol dibutyrate andtriethylene glycol dipropionate; and mixtures thereof. Preferred lowmolecular weight plasticizers for the continuous hydrophilic phase aretriethyl citrate, diethyl phthalate, and dioctyl adipate, with dioctyladipate most preferred.

The properties of the composition of the invention are readilycontrolled by adjusting one or more parameters during fabrication. Forexample, the adhesive strength of the composition can be controlledduring manufacture in order to increase, decrease, or eliminateadhesion. This can be accomplished by varying type and/or amount ofdifferent components, or by changing the mode of manufacture. Also, withrespect to the fabrication process, compositions prepared using aconventional melt extrusion process are generally, although notnecessarily, somewhat less tacky than compositions prepared using asolution cast technique. Furthermore, the degree to which the hydrogelcomposition will swell upon contact with water can be varied byselecting different water-swellable polymers, and, in those compositionscontaining a continuous hydrophilic phase, by adjusting the ratio of thewater-swellable, water-insoluble polymers to the hydrophilicpolymer/complementary plasticizer blend. These compositions may vary inappearance from clear, transparent to translucent to opaque. Inaddition, certain compositions may be rendered translucent by changingthe relative quantities of the components in the hydrophilic phase(e.g., by decreasing the amount of the cellulose ester), or by changingthe fabrication method (translucent hydrogels are more readily obtainedusing solution casting than melt extrusion). In this manner, thetranslucent composition allows the user to observe the therapeutic orcosmetic (e.g., whitening) process while it is occurring and determinewhen the desired effect has been obtains, for example when the teethhave been sufficiently whitened.

III. Active Agents

The composition can also include any pharmaceutically active agentuseful in treating physiological conditions involving the teeth andsurrounding tissue, as well as skin and mucosal tissues. The activeagent can be any substance that can be released from the composition totreat an undesirable physiological condition. Undesirable, physiologicalconditions involving the teeth or surrounding tissue which are amenableto treatment with the present device include: halitosis; periodontal andoral infections; periodontal lesions; dental caries or decay;gingivitis; and other periodontal diseases.

Such agents would be present in a cosmeceutically or therapeuticallyeffective amount. These include, by way of example and not limitation,adrenergic agents, adrenocortical steroids, adrenocortical suppressants,alcohol deterrents, aldosterone antagonists, amino acids, ammoniadetoxicants, anabolic agents, analeptic agents, analgesic agents,androgenic agents, anesthetic agents, anorectic compounds, anorexicagents, antagonists, anterior pituitary activators and anteriorpituitary suppressants, anthelmintic agents, anti-acne agents,anti-adrenergic agents, anti-allergic agents, anti-amebic agents,anti-androgen agents, anti-anemic agents, anti-anginal agents,anti-anxiety agents, anti-arthritic agents, anti-asthmatic agents,anti-atherosclerotic agents, antibacterial agents, anticholelithicagents, anticholelithogenic agents, anticholinergic agents,anticoagulants, anticoccidal agents, anticonvulsants, antidepressants,antidiabetic agents, antidiarrheal agents, antidiuretics, antidotes,antidyskinetics agents, anti-emetic agents, anti-epileptic agents,anti-estrogen agents, antifibrinolytic agents, antifungal agents,antiglaucoma agents, antihemophilic agents, antihemophilic Factor,antihemorrhagic agents, antihistaminic agents, antihyperlipidemicagents, antihyperlipoproteinemic agents, antihypertensives,antihypotensives, anti-infective agents, anti-inflammatory agents,antikeratinizing agents, antimalarial agents, antimicrobial agents,antimigraine agents, antimitotic agents, antimycotic agents,antinauseants, antineoplastic agents, anti-cancer supplementarypotentiating agents, antineutropenic agents, antiobsessional agents,antiparasitic agents, antiparkinsonian drugs, antipneumocystic agents,antiproliferative agents, antiprostatic hypertrophydrugs, antiprotozoalagents, antipruritics, antipsoriatic agents, antipsychotics,antirheumatic agents, antischistosomal agents, antiseborrheic agents,antispasmodic agents, antithrombotic agents, antitussive agents,anti-ulcerative agents, anti-urolithic agents, antiviral agents,appetite suppressants, benign prostatic hyperplasia therapy agents,blood glucose regulators, bone resorption inhibitors, bronchodilators,carbonic anhydrase inhibitors, cardiac depressants, cardioprotectants,cardiotonic agents, cardiovascular agents, choleretic agents,cholinergic agents, cholinergic agonists, cholinesterase deactivators,coccidiostat agents, cognition adjuvants and cognition enhancers,depressants, diagnostic aids, diuretics, dopaminergic agents,ectoparasiticides, emetic agents, enzyme inhibitors, estrogens,fibrinolytic agents, free oxygen radical scavengers, gastrointestinalmotility agents, glucocorticoids, gonad-stimulating principles, hairgrowth stimulants, hemostatic agents, histamine H2 receptor antagonists,hormones, hypocholesterolemic agents, hypoglycemic agents, hypolipidemicagents, hypotensive agents, HMGCoA reductase inhibitors, immunizingagents, immunomodulators, immunoregulators, immunostimulants,immunosuppressants, impotence therapy adjuncts, inhibitors, keratolyticagents, LHRH agonists, liver disorder treatments, luteolysin agents,memory adjuvants, mental performance enhancers, mood regulators,mucolytics, mucosal protective agents, mydriatic agents, nasaldecongestants, neuroleptic agents, neuromuscular blocking agents,neuroprotective agents, NMDA antagonists, non-hormonal sterolderivatives, oxytocic agents, plasminogen activators, plateletactivating factor antagonists, platelet aggregation inhibitors,post-stroke and post-head trauma treatments, potentiators, progestins,prostaglandins, prostate growth inhibitors, prothyrotropin agents,psychotropic agents, radioactive agents, regulators, relaxants,repartitioning agents, scabicides, sclerosing agents, sedatives,sedative-hypnotic agents, selective adenosine A1 antagonists, serotoninantagonists, serotonin inhibitors, serotonin receptor antagonists,steroids, stimulants, suppressants, synergists, thyroid hormones,thyroid inhibitors, thyromimetic agents, tranquilizers, unstable anginaagents, uricosuric agents, vasoconstrictors, vasodilators, vulneraryagents, wound healing agents, xanthine oxidase inhibitors, and the like.

In one embodiment, the above-described hydrogel composition contains awhitening agent and thereby acts as a delivery system when applied tothe teeth. The release of whitening agents “loaded” into the presenthydrogel compositions typically involves both absorption of water anddesorption of the agent via a swelling-controlled diffusion mechanism.Whitening agent-containing hydrogel compositions may be employed in amanner similar to that of topical pharmaceutical formulations, forexample.

Suitable tooth whitening agents include peroxides, metal chlorites,perborates, percarbonates, peroxyacids, and combinations thereof.Suitable peroxide compounds include hydrogen peroxide, calcium peroxide,carbamide peroxide, and mixtures thereof. The preferred peroxides arehydrogen and carbamide peroxide. Other suitable peroxides includeorganic peroxides, including but not limited to dialkyl peroxides suchas t-butyl peroxide and 2,2 bis(t-butylperoxy)propane, diacyl peroxidessuch as benzoyl peroxide and acetyl peroxide, peresters such as t-butylperbenzoate and t-butyl per-2-ethylhexanoate, perdicarbonates such asdicetyl peroxy dicarbonate and dicyclohexyl peroxy dicarbonate, ketoneperoxides such as cyclohexanone peroxide and methylethylketone peroxide,and hydroperoxides such as cumene hydroperoxide and tert-butylhydroperoxide. The whitening agent is preferably a peroxide, such ashydrogen peroxide or carbamide peroxide, and most preferably is hydrogenperoxide.

Suitable metal chlorites include calcium chlorite, barium chlorite,magnesium chlorite, lithium chlorite, sodium chlorite, and potassiumchlorite; hypochlorite and chlorine dioxide. The preferred chlorite issodium chlorite.

In another embodiment, the pharmaceutically active agent can be, forexample, an non-steroidal anti-inflammatory/analgesic; steroidalanti-inflammatory agents; local anesthetics; bactericides/disinfectants;antibiotics; antifungals; tooth desensitizing agents; fluorideanticavity/antidecay agents; anti-tartar/anti-calculus agents; enzymeswhich inhibit the formation of plaque, calculus or dental caries;abrasive agents such as pyrophosphates; metal chelators such asethylenediaminetetraacetic acid, tetrasodium salt; anti-oxidants such asbutylated hydroxyanisole; butylated hydroxy toluene; nutritionalsupplements for local delivery to the teeth and surrounding tissue; andso forth.

Suitable non-steroidal anti-inflammatory/analgesic agents includeacetaminophen; methyl salicylate; monoglycol salicylate; aspirin;mefenamic acid; flufenamic acid; indomethacin; diclofenac; alclofenac;diclofenac sodium; ibuprofen; flurbiprofen; fentizac; bufexamac;piroxicam; phenylbutazone; oxyphenbutazone; clofezone; pentazocine;mepirizole; and tiaramide hydrochloride.

Suitable steroidal anti-inflammatory agents include hydrocortisone;prednisolone; dexamethasone; triamcinolone acetonide; fluocinoloneacetonide; hydrocortisone acetate; prednisolone acetate;methylprednisolone; dexamethasone acetate; betamethasone; betamethasonevalerate; flumetasone; fluorometholone; budesonide; and beclomethasonedipropionate.

Suitable local anesthetics include dibucaine hydrochloride; dibucaine;lidocaine hydrochloride; lidocaine; benzocaine; p-buthylaminobenzoicacid 2-(diethylamino) ethyl ester hydrochloride; procaine hydrochloride;tetracaine hydrochloride; chloroprocaine hydrochloride; oxyprocainehydrochloride; mepivacaine; cocaine hydrochloride; and piperocainehydrochloride.

Suitable bactericides/disinfectants include thimerosol; phenol; thymol;benzalkonium chloride; benzethonium chloride; chlorhexidine; providoneiodide; cetylpyridinium chloride; eugenol, and trimethylammoniumbromide.

Suitable antibiotics include penicillin; meticillin; oxacillin;cefalotin; cefaloridin; erythromycin; lincomycin; tetracycline;chlortetracycline; oxytetracycline; metacycline; chloramphenicol;kanamycin; streptomycin; gentamicin; bacitracin; and cycloserine.Suitable antifungal drugs include amphotericin; clotrimazole; econazolenitrate; fluconazole; griseofulvin; itraconazole; ketoconazole;miconazole; nystatin; terbinafine hydrochloride; undecenoic acid; andzinc undecenoate.

Suitable tooth-desensitizing agents include potassium nitrate andstrontium chloride. Suitable fluoride anticavity/antidecay agentsinclude sodium fluoride, potassium fluoride and ammonium fluoride.

Additional whitening agents include anti-tartar/anti-calculus agents,including phosphates such as pyrophosphates, polyphosphates,polyphosphonates (e.g., ethane-1-hydroxy-1,1-diphosphonate,1-azacycloheptane-1,1-diphosphonate, and linear alkyl diphosphonates),and salts thereof; linear carboxylic acids; and sodium zinc citrate; andmixtures thereof. Preferred pyrophosphate salts are the dialkali metalpyrophosphate salts, tetra-alkali metal pyrophosphate salts; and thehydrated or unhydrated forms of disodium dihydrogen pyrophosphate(Na₂H₂P₂O₇), tetrasodium pyrophosphate (Na₄P₂O₇), and tetrapotassiumpyrophosphate (K₄P₂O₇). The pyrophosphate salts are described in moredetail in Kirk & Othmer, Encyclopedia of Clinical Technology ThirdEdition, Volume 17, Wiley-Interscience Publishers (1982), the entiredisclosure of which is herein incorporated by reference in its entirety.Optionally, whitening agents can also include tartar dissolving agentssuch as betaines, amine oxides and quaternaries, as described in U.S.Pat. No. 6,315,991 to Zofchak.

Enzymatic agents that would act to inhibit the formation of plaque,calculus or dental caries would also be useful in the compositions. Theenzymatic agents can be stored together with the whitening agent, orthey can be positioned in a different layer within a multiple layersystem as described herein. Suitable enzymes include: proteases thatbreak down salivary proteins which are absorbed onto the tooth surfaceand form the pellicle, or first layer of plaque; lipases which destroybacteria by lysing proteins and lipids which form the structuralcomponent of bacterial cell walls and membranes; dextranases,glucanohydrolases, endoglycosidases, and mucinases which break down thebacterial skeletal structure which forms a matrix for bacterial adhesionto the tooth; and amylases which prevent the development of calculus bybreaking-up the carbohydrate-protein complex that binds calcium.Preferred enzymes include any of the commercially available proteases;dextranases; glucanohydrolases; endoglycosidases; amylases; mutanases;lipases; mucinases; and compatible mixtures thereof. In someembodiments, an enzymatic whitening agent may be utilized.

Optionally, an enzymatic whitening agent is a peroxidase such thatperoxide is generated in situ. When an enzymatic whitening or antiplaqueagent is incorporated into the composition, the composition should besuch that the enzyme is maintained in its active form, e.g., the pHshould be approximately neutral, and peroxide may be omitted orcontained in a separate layer.

Suitable nutritional supplements for local delivery to the teeth andsurrounding tissue include vitamins (e.g., vitamins C and D, thiamine,riboflavin, calcium pantothenate, niacin, folic acid, nicotinamide,pyridoxine, cyanocobalamin, para-aminobenzoic acid, and bioflavonoids);and minerals (e.g., calcium, phosphorus, fluoride, zinc, manganese, andpotassium); and mixtures thereof. Vitamins and minerals useful in thepresent invention are disclosed in Drug Facts and Comparisons (looseleaf drug information service), Wolters Kluer Company, St. Louis, Mo.,1997, pp 3-17; the entire disclosure of which is herein incorporated byreference.

The composition can also include any cosmetically active agent to effecta desired change in the appearance of the teeth or surrounding tissue,or which imparts a socially desirable characteristic to the user, suchas fresh breath. For example, a cosmetically active agent can be abreath freshener or an agent which effects whitening or bleaching of theteeth. Recognizing that in some cultures or in certain segments ofWestern society coloration of the teeth may be significant or desirable,the cosmetically active agent can also be any agent which imparts acolor or tint to the teeth.

Additional whitening agents may be included in the composition. Forexample, surfactants such as detergents, may also be present, and willwork together with the whitening agents described above to provide abrighter appearance to the teeth.

In any of these embodiments, a tooth whitening composition of theinvention preferably includes a peroxide for whitening the teeth, andmay also include conventional additives such as fillers, preservatives,pH regulators, softeners, thickeners, colorants, pigments, dyes,refractive particles, stabilizers, toughening agents, pharmaceuticalagents, flavoring or breath freshening agents, and permeation enhancers.In those embodiments wherein adhesion is to be reduced or eliminated,conventional detackifying agents may also be used. These additives, andamounts thereof, are selected in such a way that they do notsignificantly interfere with the desired chemical and physicalproperties of the tooth whitening composition, or interfere with thedelivery of the tooth whitening agent can be included in thecomposition. Such additional ingredients include coloring compounds,food additives, flavorants, sweeteners, and preservatives.

Any natural or synthetic flavorant or food additive, such as thosedescribed in Chemicals Used in Food Processing, Pub. No. 1274, NationalAcademy of Sciences, pages 63-258 (the entire disclosure of which isherein incorporated by reference) can be used. Suitable flavorantsinclude wintergreen, peppermint, spearmint, menthol, fruit flavors,vanilla, cinnamon, spices, flavor oils and oleoresins, as known in theart, as well as combinations thereof. The amount of flavorant employedis normally a matter of preference, subject to such factors as flavortype, individual flavor, and strength desired. Preferably, thecomposition comprises from about 0.1-5 wt % flavorant.

Sweeteners useful in the present invention include sucrose, fructose,aspartame, xylitol and saccharine. Preferably, the composition comprisessweeteners in an amount from about 0.001-5.0 wt %.

The suitable substrate can be translucent so that the composition isunobtrusive when worn. However, the substrate or the composition canoptionally be colored, so that the composition is easily seen when worn.Preferably, if coloring is desired, the color will be present in thesubstrate. For example, the substrate can be colored with bright orvibrant colors which a consumer may find pleasing. The substrate cantherefore comprise a colorizing compound, such as, for example, a dye,pigment or substance that can impart color when added to the materialforming the substrate.

For example, colorizing compounds of the type commonly used with a food,drugs, or cosmetics in connection with the human body, especially coloradditives permitted for use in foods which are classified as“certifiable” or “exempt from certification,” can be used to color thesubstrate. The colorizing compounds used to color the substrate can bederived from natural sources such as vegetables, minerals or animals, orcan be man-made counterparts of natural derivatives.

Colorizing compounds presently certified under the Food Drug & CosmeticAct for use in food and ingested drugs include dyes such as FD&C Red No.3 (sodium salt of tetraiodofluorescein); Food Red 17 (disodium salt of6-hydroxy-5-{(2-methoxy-5-methyl-4-sulphophenyl)azo}-2-naphthalenesulfonicacid); Food Yellow 13 (sodium salt of a mixture of the mono anddisulfonic acids of quinophthalone or 2-(2-quinolyl)indanedione); FD&CYellow No. 5 (sodium salt of4-p-sulfophenylazo-1-p-sulfophenyl-5-hydroxypyrazole-3 carboxylic acid);FD&C Yellow No. 6 (sodium salt ofp-sulfophenylazo-B-napthol-6-monosulfonate); FD&C Green No. 3 (disodiumsalt of4-{[4-(N-ethyl-p-sulfobenzylamino)-phenyl]-(4-hydroxy-2-sulfonium-phenyl)-methylene}-[1-(N-ethyl-N-p-sulfobenzyl)-3,5-cyclohexadienimine]);FD&C Blue No. 1 (disodium salt ofdibenzyldiethyl-diaminotriphenylcarbinol trisulfonic acid anhydrite);FD&C Blue No. 2 (sodium salt of disulfonic acid of indigotin); FD&C RedNo. 40; Orange B; and Citrus Red No. 2; and combinations thereof invarious proportions.

Colorizing compounds exempt from FDA certification include annattoextract; beta-apo-8′-carotenal; beta-carotene; beet powder;canthaxanthin; caramel color; carrot oil; cochineal extract (carmine);toasted, partially defatted, cooked cottonseed flour; ferrous gluconate;fruit juice; grape color extract; grape skin extract (enocianina);paprika; paprika oleoresin; riboflavin; saffron; turmeric; turmericoleoresin; vegetable juice; and combinations thereof in variousproportions.

The form of the colorizing compound for use in the compositionpreferably includes dye form additives, but may also include lake formswhich are compatible with the material comprising the substrate. Watersoluble dyes, provided in the form of powders, granules, liquids orother special-purpose forms, can be used in accordance with the presentmethod. Preferably, the “lake”, or water insoluble form of the dye, isused for coloring the substrate. For example, if a suspension of acolorizing compound is to be used, a lake form additive can be employed.Suitable water insoluble dye lakes prepared by extending calcium oraluminum salts of FD&C dyes on alumina include FD&C Green #1 lake, FD&CBlue #2 lake, FD&C R&D #30 lake and FD&C # Yellow 15 lake.

Other suitable colorizing compounds include non-toxic, water insolubleinorganic pigments such as titanium dioxide; chromium oxide greens;ultramarine blues and pinks; and ferric oxides. Such pigments preferablyhave a particle size in the range of about 5-1000 microns, morepreferably about 250-500 microns.

The concentration of the colorizing compound in the substrate ispreferably from about 0.05-10 wt %, and is more preferably from about0.1-5 wt %.

More than one colorizing compound can be present in the substrate, sothat multiple colors are imparted therein. These multiple colors can bepatterned into stripes, dots, swirls, or any other design which aconsumer may find pleasing. The colorizing compound can also be usedwith other appearance-enhancing substances such as glitter particles.

Absorbent fillers may be advantageously incorporated to control thedegree of hydration when the adhesive is on the tooth surface. Suchfillers can include microcrystalline cellulose, talc, lactose, kaolin,mannitol, colloidal silica, alumina, zinc oxide, titanium oxide,magnesium silicate, magnesium aluminum silicate, hydrophobic starch,calcium sulfate, calcium stearate, calcium phosphate, calcium phosphatedihydrate, clays such as laponite, woven and non-woven paper and cottonmaterials. Other suitable fillers are inert, i.e., substantiallynon-adsorbent, and include, for example, polyethylenes, polypropylenes,polyurethane polyether amide copolymers, polyesters and polyestercopolymers, nylon and rayon. A preferred filler is colloidal silica,e.g., Cab-O-Sil® (Cabot Corporation, Boston Mass.).

Preservatives include, by way of example, p-chloro-m-cresol, phenylethylalcohol, phenoxyethyl alcohol, chlorobutanol, 4-hydroxybenzoic acidmethylester, 4-hydroxybenzoic acid propylester, benzalkonium chloride,cetylpyridinium chloride, chlorohexidine diacetate or gluconate,ethanol, and propylene glycol.

Compounds useful as pH regulators include, but are not limited to,glycerol buffers, citrate buffers, borate buffers, phosphate buffers, orcitric acid-phosphate buffers may also be included so as to ensure thatthe pH of the hydrogel composition is compatible with that of theenvironment of the mouth and will not leach minerals from the surface ofthe teeth. In order to optimize whitening without demineralization ofthe teeth, calcium and/or fluoride salts can be included in thecomposition.

Suitable softeners include citric acid esters, such as triethylcitrateor acetyl triethylcitrate, tartaric acid esters such as dibutyltartrate,glycerol esters such as glycerol diacetate and glycerol triacetate;phthalic acid esters, such as dibutyl phthalate and diethyl phthalate;and/or hydrophilic surfactants, preferably hydrophilic non-ionicsurfactants, such as, for example, partial fatty acid esters of sugars,polyethylene glycol fatty acid esters, polyethylene glycol fatty alcoholethers, and polyethylene glycol sorbitan-fatty acid esters.

Preferred thickeners herein are naturally occurring compounds orderivatives thereof, and include, by way of example: collagen;galactomannans; starches; starch derivatives and hydrolysates; cellulosederivatives such as methyl cellulose, hydroxypropylcellulose,hydroxyethyl cellulose, and hydroxypropyl methyl cellulose; colloidalsilicic acids; and sugars such as lactose, saccharose, fructose andglucose. Synthetic thickeners such as polyvinyl alcohol,vinylpyrrolidone-vinylacetate-copolymers, polyethylene glycols, andpolypropylene glycols may also be used.

The substrate can also be embedded or decorated with decorative itemssuch as beads, rhinestones, or the like, as long as these items do notinterfere with the visco-elastic properties of the substrate requiredfor proper deformation of the composition onto the teeth, as describedabove. The substrate can also display letters, words, or images designedto be pleasing or attractive to a consumer.

IV. Fabrication Processes

The compositions of the invention are generally melt extrudable, andthus may be prepared using a simple blending and extruding process. Thecomponents of the composition are weighed out and then admixed, forexample using a Brabender or Baker Perkins Blender, generally althoughnot necessarily at an elevated temperature, e.g., about 90-140° C.Solvents or water may be added if desired. The resulting composition canbe extruded using a single or twin extruder, or pelletized.Alternatively, the components of the composition can be melted one at atime, and then mixed prior to extrusion. Preferably the composition isextruded directly onto a suitable substrate such as a backing layer or areleasable liner, and then pressed. The thickness of the resultinghydrogel-containing film, for most purposes, will be in the range ofabout 0.050-0.80 mm, more usually in the range of about 0.37-0.47 mm.

Alternatively, the compositions may be prepared by solution casting, byadmixing the components of the composition in a suitable solvent, e.g.,a volatile solvent such as ethyl acetate, or lower alkanols (e.g.,ethanol, isopropyl alcohol, etc.) are particularly preferred, at aconcentration typically in the range of about 35-60% w/v. The solutionis cast onto a suitable substrate such as a backing layer or releasableliner, as above. Both admixture and casting are preferably carried outat ambient temperature. The substrate coated with the film is then bakedat a temperature in the range of about 80-100° C., optimally about 90°C., for time period in the range of about one to four hours, optimallyabout two hours. Accordingly, one embodiment of the invention is amethod for preparing a hydrogel film suitable for incorporation into acomposition of the invention, which involves the following steps:preparing a solution of a water-swellable, water-insoluble polymer or awater-soluble polymer, a hydrophilic polymer, a complementary oligomercapable of hydrogen bonding to the hydrophilic polymer, and a secondwater-swellable, water-insoluble polymer, in a solvent; depositing alayer of the solution on a substrate to provide a coating thereon; andheating the coated substrate to a temperature in the range of about80-100° C. for a time period in the range of about 1-4 hours, therebyproviding a hydrogel film on the substrate.

When tacky hydrogel compositions are desired, melt extrusion is thepreferred process, although solution casting may still be used. Forpreparation of substantially nontacky compositions, solution casting ispreferred. Also, melt extrusion can be used for any of the compositionsof the invention. Also, either melt extrusion or solution castingtechniques can be used to prepare translucent compositions, althoughsolution casting is typically preferred for these embodiments.Accordingly, another embodiment of the invention is a method of forminga composition, which involves the following steps: melt processingthrough an extruder a mixture of a water-swellable, water-insolublepolymer or a water-soluble polymer, a hydrophilic polymer, acomplementary oligomer capable of hydrogen bonding to the hydrophilicpolymer, and a second water-swellable, water-insoluble polymer, to forman extruded composition; extruding the composition as a film of desiredthickness onto a suitable substrate; and, when cooled, and loading thefilm with an aqueous solution of the active agent such as a peroxide toobtain a concentration of whitening agent of from about 1-20 wt %.

The invention also contemplates having a multiple layer system thatincludes one or more additional hydrogel or non-hydrogel layers. Forexample, it may be desirable to include additional active agents thatmay not be compatible with the primary active agent during storage. Inthis manner, one layer can be the primary active agent-containinghydrogel layer and the other layer(s) can contain additional actives.These other layers can be made of the hydrogel composition describedherein, or any other biocompatible formulation known in the art (e.g.,polyisobutylene, dimethyl siloxane, ethylene vinyl acetate,polyvinylacetate, cellulose acetate, butyrate, propionate, ethylcellulose and water insoluble acrylates). In addition, depending onordering of the layers, it may be desired to have a tacky layer, e.g.,the layer to be positioned directly on the teeth, and a non-tacky layer,e.g., the outer layer that is positioned nearest the lips. Anotheradvantage of having multiple layer system is that the ratio of polymersused in the outermost layer can be varied to achieve a non-tacky layersso as to avoid having to include a separate backing layer in theproduct.

In one embodiment, the composition comprises: an outer substrate thatserves as the external surface of the composition following applicationto the tooth, oral tissue, skin or mucosal surface; a surface contactadhesive layer adhered thereto, which generally will be an adhesivecomposition of the invention, optionally containing additional activeagents; and a removable release liner. Upon removal of a release liner,for example, the composition is applied to the surface, e.g., the teeth,to be treated, and placed on the surface so that the oralsurface-contacting layer is in contact. In another embodiment, thecomposition is packaged without a backing layer or a release liner.Accordingly, once removed from the packaging, the composition is readyto be applied to the body surface.

The substrate is the primary structural element and provides thecomposition with support, either during manufacture or during use. Thematerial used for the substrate should be inert and incapable ofabsorbing the hydrogel composition. Also, the material used for thesubstrate should permit the device to follow the contours of the teethor other body surface and be worn comfortably in the mouth withoutrubbing or otherwise irritating the lips or tongue. Examples ofmaterials useful for the substrate are polyesters, polyethylene,polypropylene, polyurethanes and polyether amides. The substrate ispreferably in the range of about 15-250 microns in thickness, and may,if desired, be pigmented, metallized, or provided with a matte finishsuitable for writing.

In one embodiment, the substrate is preferably although not necessarilyocclusive (i.e., not “breathable”), and does not allow any active agentin the composition to leak through the layer, and contact the mucousmembranes of the mouth and gums. When ready for use, the composition ispre-moistened so that the tackiness is increased and the compositionwill adhere to the teeth. One advantage of this embodiment is that theactive agent cannot substantially leak out through the substrate andcause irritation in those individuals sensitive to the active agent orto any unpleasant flavor or sensation.

Other suitable substrate materials can be non-polymeric materials suchas waxes (e.g., microcrystalline or paraffin waxes) or a wax/foamlaminate. Paraffin waxes are low molecular weight straight-chainhydrocarbons, with melting points of about 48-75° C. and molecularweights of about 300-1400 g/mol, and are typically made by theFischer-Tropsch synthesis. Microcrystalline waxes are flexible andamorphous-like in appearance and tend to have a higher tensile strengthand smaller crystal size than paraffin waxes. Microcrystalline waxestypically have melting points of about 60-95° C. and molecular weightsof about 580-700 g/mol, and predominantly contain branched-chainhydrocarbons and some ring-type compounds, although straight-chainhydrocarbons can be present. The substrate material can also be anopen-cell foam such as a polyurethane, polystyrene or polyethylene foam.

Alternatively, in another embodiment, the substrate is non-occlusive,and therefore can fully hydrate in situ, in position on the teeth orother body surface.

The release liner is a disposable element that serves to protect thesystem prior to application. The release liner should be formed from amaterial impermeable to the active agent and hydrogel composition, andthat is easily stripped from the contact adhesive. Release liners aretypically treated with silicone or fluorocarbons, and are commonly madefrom polyesters and polyethylene terephthalate.

A preferred composition is typically prepared using a acrylate polymersas the first and second water-insoluble, water-swellable polymers; and ablend of polyvinylpyrrolidone and polyethylene glycol as the blend of ahydrophilic polymer and a complementary oligomer capable of hydrogenbonding to the hydrophilic polymer.

An adhesive film of the composition can be manufactured by thermallymelting and mixing the above components together at temperatures rangingfrom about 100-170° C. The film is extruded to a desired thickness on asuitable substrate. Alternatively, the components can be dissolved in asingle or mixture of solvents, and the solution can be cast on areleasing or backing film. The solvents are then evaporated to obtain ahydrogel film.

One method of loading the composition with the active agent compriseslayering a desired active agent, e.g., a tooth whitening agent, inaqueous solution onto the surface of the hydrogel placed on a suitablesubstrate, or to place the active agent directly on the substrate. Therelease liner is then assembled on top of the composition, forming asandwich structure, and the solution containing the whitening agent isabsorbed into the composition due to its water-swellable properties.Alternatively, the composition layered onto the substrate can besubmerged in a solution containing the desired concentration ofwhitening agent, and the solution absorbed into the composition. Bymeasuring the rate of weight gain on absorbing the liquid, the percentloading of the composition with the active agent can be determined andcontrolled.

Another approach to loading the active agent into the composition is toadd the active agent as a solid or as a solution to the compositiondissolved in solvent. The mixture is then cast as usual onto a suitablesubstrate and allowed to dry, although a lower drying temperature isdesired when using this method of loading. Compositions prepared in thismanner can be dried at ambient temperature for a time period rangingfrom about 1 hour to several days.

A typical film thickness is from about 0.050-0.80 mm, preferably0.25-0.50 mm. The thickness of the film is not critical, and can bevaried according to the concentration of whitening agent incorporatedinto the film, the length of time the film is to be exposed to theteeth, the level of comfort desired by the wearer, and the degree ofstaining that it is desired to rectify.

V. Methods of Use

In practice, the compositions can be used simply by removing the productfrom its package, removing a release liner (when included) and applyingthe adhesive layer to the teeth that it is desired to whiten (or to anyskin or mucosal body surface if another utility of the whitening agentis to be used or if another active agent is to be used). The systemsdescribed herein can be provided in a variety of sizes, so that thecomposition can be applied to the entirety or any portion of a tooth, toany number of teeth at one time, or to any portion of the oral cavity.The substrate, when occlusive, reduces or prevents leakage of the activeagent, from the composition, while the user wears the composition forthe desired amount of time. The composition can be maintained in thedesired location for as little time as a few minutes, several hours, allday or overnight, and then removed when the desired degree of whiteningor the desired therapeutic or cosmetic effect has been achieved. Ifdesired, a translucent composition can be provided, and is worn withoutbeing obtrusive or noticeable to others. The system can also be designedwithout an active ingredient and finds utility as a protective dressingfor an oral surface, e.g., canker sore, cold sore, etc or as a wounddressing.

The composition can be worn for an extended period of time, but willtypically be worn for a predetermined period of time of from about 10minutes to about 24 hours. For tooth whitening applications, a preferredtime period is from about 10 minutes to about 8 hours (e.g., overnight),with 30 minutes to about 1 hour also being a preferred embodiment. Forother active agents, a therapeutically or cosmeceutically effective timecan be readily determined based upon the active agent that is being usedas well as the condition being treated.

A user can form the composition around the upper or lower teeth or otheroral tissue by applying normal manual pressure to the substrate with thetips of the fingers and thumbs, optionally by moistening the compositionprior to application. Assuming the surface area of the average adultfinger or thumb tip is approximately one square centimeter, the normalpressure generated by the finger and thumb tips is about 100,000-150,000Pascals (i.e., about 3 lbs. or 1.36 kg) per square centimeter. Thepressure is typically applied to the composition by each finger andthumb tip for about one or two seconds. Once the pressure applied to thesubstrate by the tips of the fingers and thumbs is removed, thecomposition remains in the shape of, and adherent to, the surface of theteeth and adjoining soft tissue onto which it was formed.

When the user is ready to remove the composition, the composition can beremoved simply by peeling it away from the surface of the teeth or otheroral or body surface. If desired, the composition can be re-adhered foradditional treatment time. Any residue left behind is minimal, and canbe removed using conventional tooth or oral cavity cleansing methods.

In one embodiment of the invention, the composition is a solid and is apressure sensitive adhesive and absorbs water. This can be achieved bymanufacturing the phase separating film-forming composition prior toapplication to the body surface. The solid formulations made in thismanner could then be packaged and removed from the package prior to use.

The composition is preferably applied as a non-solid composition, forexample applied as a liquid or gel. For example, the user can extrudethe composition from a tube onto a finger for application to the teethor other body surface, extrude the composition from a tube directly ontothe teeth, apply the composition by means of a brush or otherapplicator, and so forth. After the evaporation of solvent, the liquidor gel composition dries to form a matrix-type polymer film or gel onthe body surface. In one embodiment of this liquid or gel film-formercomposition, the hydrogel contains sufficient water or other solvent toprovide flowable property. In another embodiment of this composition,the polymer components of the liquid or gel composition are soluble in awater-ethanol mixture both at ambient temperature and at refrigerationtemperatures of about 4° C., and are miscible upon solvent evaporation.In yet another embodiment of this liquid or gel film-former composition,the polymeric composition has a Lower Critical Solution Temperature ofabout 36° C. in an ethanol-water mixture. The resulting film (aftersolvent evaporation) is preferably insoluble or slowly soluble in salivaat body temperature so as to provide long lasting contact between thehydrogen peroxide and the dental enamel. Finally, the hydrogen peroxideshould be stable both in the liquid or gel composition, as well aswithin polymer film upon drying.

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of polymer chemistry, adhesivemanufacture, and hydrogel preparation, which are within the skill of theart. Such techniques are fully explained in the literature.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, theforegoing description, as well as the examples that follow, are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages and modifications will be apparent to those skilled in theart to which the invention pertains. All patents, patent applications,journal articles and other references cited herein are incorporated byreference in their entireties.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the compounds of the invention, and are not intended tolimit the scope of what the inventors regard as their invention. Effortshave been made to ensure accuracy with respect to numbers (e.g.,amounts, temperatures, etc.) but some errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in degrees Celsius (° C.), and pressure is at or nearatmospheric.

The following abbreviations and tradenames are used in the examples:

Eudragit L 100-55 methacrylic acid copolymer, (Rohm America Inc.) PEGpolyethylene glycol 400 PVP30 Plasdone ® K30 polyvinylpyrrolidone (ISP)PVP90 Kollidon ® 90F polyvinylpyrrolidone (BASF)

EXAMPLES Example 1 Preparation of a Solid Composition

One embodiment of a composition for tooth whitening was prepared fromthe following ingredients using a melt extrusion process:

Eudragit L 100-55  9 wt % PVP90 44 wt % PEG 22 wt % Hydrogen peroxide  6wt % Water, stabilizers, pH modulators 19 wt %

The ingredients were melt processed in a Brabender single screw extruderas follows: The Eudragit L 100-55 was added to the extruder first,followed by PVP90 and PEG, at a temperature of 100 to 150° C. Thecomposition was extruded to a thickness of 0.35 mm between twopolyethylene terephthalate release liners. Hydrogen peroxide solutionwas added to the extruded film.

Example 2 In Vitro Release of Hydrogen Peroxide from a Solid Composition

The release of hydrogen peroxide from the tooth whitening compositionsof the invention in vitro, in pH 7.0 buffer, was investigated andcompared with the peroxide released from a commercial product, CrestWhitestrips (a product of the Proctor & Gamble Co., Cincinnati, Ohio andreferred to as the “Crest product”). The Crest product contains 5.3%hydrogen peroxide in a Carbopol 956 gel on a thin polyethylene film.

The in vitro release of hydrogen peroxide from the compositionscontaining 3%, 6% or 9% peroxide (formulated as set forth in Example 1)was compared with the release of hydrogen peroxide from the Crestproduct. The test composition or the Crest product was allowed torelease peroxide into solution through filter paper, and the peroxidewas measured using standard analytical techniques. For the Crestproduct, the peroxide levels observed decreased to baseline within about30 minutes. This data is similar to published data (Pagel, P. A., et al.(2000) Vital Tooth Whitening with a Novel Hydrogen Peroxide StripSystem: Design, Kinetics, and Clinical Response. Compendium, Suppl. 29,Vol. 21: S10-S15).

The tooth whitening compositions of the invention released peroxide at arate proportional to the starting concentration. The compositions of theinvention were also found to release peroxide at a higher rate than theCrest product at all times the peroxide content was tested: 5, 30 and 60minutes. The peroxide release for the composition containing 6%peroxide, which is close to the Crest product, was approximately 7.5, 24and 10 times greater as the release rate for the Crest product at eachtime point, respectively. The peroxide release for the compositioncontaining 3% peroxide, was approximately 3, 7 and 5 times greater asthe release rate for the Crest product at each time point, respectively.

Example 3 Efficacy of a Solid Composition

The efficacy of the tooth whitening compositions was tested using thefollowing procedure. A subject tested the efficacy of the toothwhitening composition prepared according to the procedure described inExample 1 by applying the composition to the lower set of teeth once aday for 1 hour, for 6 consecutive days. The shade of the subject's teethwas measured using the Professional Tooth Shade Guide before and aftertreatment of the teeth with the tooth whitening composition. On day 1,the subject's teeth were graded shade 12, and after one hour oftreatment with the tooth whitening composition, the teeth were gradedshade 10. After one hour of treatment with the tooth whiteningcomposition on day 2, the subject's teeth were graded shade 8. After onehour of treatment on day 3, the subject's teeth were graded shade 5.Similarly, after one hour of treatment on day 4, the subject's teethwere graded shade 4/5. On day 5, after one hour of treatment, thesubject's teeth were graded shade 2/3. The lightest shade was achievedafter a further one half hour of treatment on day 6, reaching a shade of2. Thus, the efficacy of the tooth whitening composition was apparent,with measurable results within one hour of treatment.

Example 4 Preparation of a Non-Solid Composition

A composition for tooth whitening was prepared from the followingingredients (Formula A):

Deionized water 35.0 wt % Ethanol 35.0 wt % Eudragit L 100-55 4.00 wt %PEG 1.00 wt % PVP90 7.00 wt % Carbamide peroxide 18.0 wt % Sodiumcitrate 0.13 wt %

The composition was mixed in a Cole-Parmer high-torque low-speed labmixer supplied with Teflon coated impeller (2 inches in diameter) asfollows. Deionized water was mixed with ethanol, followed by theaddition of PEG. Sodium citrate was then added under vigorous stirringconditions. Eudragit L 100-55 powder was added slowly (within 2-5 min)under vigorous stirring (500-600 rpm). After about 5-10 min (it is notnecessary to wait until all Eudragit is dissolved), PVP90 powder wasslowly added (within 5 min). The high stirring rate was maintained over5-10 min. Carbamide peroxide powder was added (within 1-2 min) and themixture stirred to obtain a homogeneous solution (approximately 30minutes at 800-900 rpm). The solution was then stored over a period of2-5 hours to let the air bubbles dissipate.

Example 5 Preparation of a Non-Solid Composition

A composition for tooth whitening was prepared from the followingingredients (Formula B):

Deionized water 35.0 wt % Ethanol 35.0 wt % Eudragit L 100-55 2.50 wt %PEG 1.92 wt % PVP90 6.00 wt % Carbamide peroxide 18.0 wt % SodiumCitrate 0.08 wt % Methocel A4C 1.50 wt %

The composition was mixed in a Cole-Parmer high-torque low-speed labmixer supplied with Teflon coated impeller (2 inches in diameter).Deionized water was mixed with ethanol, followed by the addition of PEG.Sodium citrate was then added under vigorous stirring conditions.Eudragit L 100-55 powder was added slowly (within 5 min) under vigorousstirring (500-600 rpm), followed by the slow (within 5 min) addition ofMethocel A4C powder under vigorous stirring (500-600 rpm). After about10 min, PVP90 powder was slowly added (within 5 min). The high stirringrate was maintained over 5-10 min. Carbamide peroxide powder was added(within 1-2 min) and the mixture stirred to obtain a homogeneoussolution (approximately 30-60 minutes at 500-800 rpm). The solution wasthen stored over a period of 2-5 hours to let the air bubbles dissipate.

Example 6 In Vitro Dissolution Comparative Study for Non-SolidComposition

The dissolution of the non-solid tooth whitening compositions preparedaccording to the procedure described in Examples 4 (Formula A) and 5(Formula B) were compared with the dissolution of a commercial product,Simply White® clear whitening gel (a product of the Colgate-PalmoliveCompany, New York, N.Y., and referred to as the “Colgate product”),which contains 18.0 wt % carbamide peroxide. The dissolution process wasstudied by means of wedge microinterferometry technique.

Formula A was found to form a sharp phase boundary separating theswollen polymer composition from the polymer solution. On the phaseboundary a sharp drop of polymer concentration (and hence polymerviscosity) was observed. No such boundary was found to exist in theColgate product/water interdiffusion zone, whose interference patternwas typical of a completely miscible system with a smooth decrease inpolymer concentration (and hence polymer viscosity) in the directionfrom the composition matrix towards water. Formula B was found to have aheterogeneous (colloidal) nature. A sharp phase boundary was formedbetween the opaque gel and the translucent aqueous solution. Formula Bwas also found to have “faster dissolving” fractions and “slowerdissolving” fractions. The slower dissolving fractions formed arelatively thin layer encompassing the opaque heterogeneous swollen gel.Contrary to the Colgate product, both Formula A and B upon contact withaqueous media are capable of forming a continuous integrated viscousswollen gel coating separated from a liquid solution by a sharp phaseboundary. Formation of the phase boundary for Formula A and B wasobserved in aqueous media with different pH ranging from 4.6 to 7.5.

Using Formulas A and B, a sharp phase boundary separating swollenpolymer from polymer solution is formed. No such boundary exists in theColgate water inter-diffusion zone whose interference pattern is typicalof the completely miscible system with a smooth decrease in polymerconcentration (and hence polymer viscosity) in the direction from theFormula A matrix and Formula B matrix towards water.

Effective mass transfer constants of water into Formula A or B andFormula A or B into water are comparable for the Colgate and Formulas Aand B. However, contrary to the Colgate product, in the case of theproduct formation of the sharp phase boundary separating swollenintegrated gel from the liquid aqueous solution is observed. Theeffective diffusion coefficient of the phase boundary is by 1-2 orderslower than those of water into Formula A or B and Formula A or B intowater. The swollen gel layer formed by Formulas A and B in the aqueousmedia is capable of playing a role of protecting coating with sustaineddissolution rate. The swollen gel also provides a mechanical support toincrease the residence time of Formulas A and B on the teeth surface.

The kinetics of the composition's penetration into water werepractically identical for Formulas A and B, whereas the kinetics of thephase boundary displacement were slower for Formula B. The effectivemass transfer constants were comparable for the Colgate product andFormulas A and B. However, in the case of Formulas A and B, a sharpphase boundary separating swollen integrated gel from the liquidsolution was observed.

In real wear conditions erosion of Formulas A and B (and hence theirwear time) was mostly dependent on two factors: 1) free interdiffusionprocesses of the composition and water (saliva) and 2) random mechanicalshear stresses imposed upon the coating during wear time (i.e. frictioncaused by movement of lips). The former factor can be considered as alimiting ideal (undisturbed) process, whereas the later can affect thewear duration in a dramatic and random way, since each coating raptureevent changes initial interdiffusion conditions dramatically (i.e.thickness of the coating and composition ingredients). Preliminary wearstudies indicated that that Formulas A and B are capable of remaining onteeth for over 10-15 minutes, whereas the Colgate product was found toremain on the teeth for over 2-3 minutes.

Example 7 Comparative In Vitro Efficacy for Non-Solid Compositions

The in vitro efficacy of the non-solid tooth whitening compositionprepared according to the procedure described in Example 4 (Formula A)was compared with the dissolution of the Colgate product.

A composition of Formula A and the Colgate product were applied on a teaspotted wall of a cup to demonstrate a “first” treatment. After 30seconds, water was introduced into the cup to cover the coated surface.After 30 minutes, the water was removed and the cup was rinsed withwater to remove any remaining gel coating on the wall. The experimentwas repeated by applying each composition on the same spot todemonstrate a “second” treatment.

Images of the treated areas were captured by digital camera and theimages obtained were converted into 256 pxl grayscale images by usingScion Image software. The images were scaled so that a pxl value of 1corresponds to an absolute white color and a value of 256 corresponds toan absolute dark color. The intermediate pxl values (from 2 to 255) thuscorresponded to intermediate colors, with darkness increasing from 1 to256. The Scion Image software was also used to measure the color density(pxl/pxl²) of the treated areas. The results, shown below, demonstratethat the composition of Formula A whitens better than the commerciallyavailable Colgate product. The higher standard deviation observed forFormula A is explained by less uniformity of the initial tea spot color.

Mean Density (pxl/pxl²) (S.D.) After 2nd Before treatment After 1sttreatment treatment Colgate product 194.3 (3.8) 185.7 (6.2) 178.0 (6.6)Formula A 198.3 (5.2) 178.6 (8.2) 167.6 (9.0)

This experiment was repeated using the non-solid tooth whiteningcomposition prepared according to the procedure described in Example 5(Formula B), except that only a “first” treatment was done.

Mean Density (pxl/pxl²) (S.D.) Before treatment After 1st treatmentColgate product 116.9 (6.6) 89.4 (6.79) Formula B 117.3 (5.1) 79.6(7.3) 

As can be seen from the in vitro data presented above, the whiteningefficacy of the composition of Formula A is appreciably superior to theColgate product, the properties of the composition of Formula B areintermediate between those of the Colgate product and Formula A.

Example 8 In Vitro Release of Hydrogen Peroxide from a Non-SolidComposition

The release of hydrogen peroxide from the non-solid tooth whiteningcomposition of Example 4 (Formula A) was compared with the dissolutionof the Colgate product. The Colgate product was cast on a release linerand dried at ambient temperature over one day. The obtained films of theColgate product, approximately 300-400μ, in thickness, were placed intoa glass beaker and 200 ml of deionized water added. The composition ofFormula A was cast onto a beaker bottom. After 2-3 minutes, 200 ml ofdeionized water was added. After an appropriate period of time, thesolution was accurately separated from the swollen residue and thehydrogen peroxide concentration was determined in accordance with theUSP titration method. The amount of hydrogen peroxide released from theColgate product and Formula A is shown below.

Percentage (wt/wt) hydrogen peroxide released Time (minutes) 1 2 3 5 1015 20 30 Colgate — 38.7 — 47.7 72.4 78.7 96.8 — product Formula A 35.035.9 59.5 67.5 71.9 — 79.2 90.0

In contrast to the Colgate product, the profile of hydrogen peroxiderelease from the film formed by Formula A was sustained andcharacterized by accelerated delivery of the active agent within thefirst five minutes. Upon 10 minutes of contact with water, Formula Areleased less hydrogen peroxide than the Colgate product. Upon 20minutes of contact with water, the Colgate product contained no hydrogenperoxide, whereas Formula A contained 20% of initially loaded hydrogenperoxide. This was evidence of stronger hydrogen peroxide bonding topolymers in Formula A than in the Colgate product. By comparing therelease and film dissolution data, it was also concluded that thecontent of the hydrogen peroxide incorporated into the Formula A filmcould be categorized as being either loosely bound hydrogen peroxide ortoughly bound hydrogen peroxide. This was in contrast to the Colgateproduct wherein all the hydrogen peroxide was loosely bound.

Example 9 Comparative In Vivo Efficacy of Non-Solid Compositions

The in vivo efficacy of the non-solid tooth whitening composition ofFormula A and Formula B were compared with the dissolution of theColgate product. The whitening efficacy of Formula A and Formula B wascompared with that of the Colgate product using the Vita Shade guidevalue-oriented scale. The study was a randomized, parallel group, doubleblind pilot study. Eleven subjects with a Vita Shade guidevalue-oriented scale of A3 or darker on a minimum of four of the sixmaxillary anterior teeth were recruited to participate in the study.

All 11 subjects were randomly assigned to one of the three treatmentgroups based upon Vita shade of the maxillary central incisors. Thesubjects received enough product for 14 days of use and were instructedto used the product twice daily over two weeks. Based upon Vitaassessments and subject interviews, it was apparent that Formula A,Formula B and the Colgate product all provided a statisticallysignificant whitening effect since the seventh days of treatment. Thebest whitening effect was observed for Formula A. Formula B showed awhitening effect that was intermediate between that of Formula A and theColgate product. Formula A demonstrated an earlier teeth whiteningeffect compared with the Colgate product.

Example 10 Preparation of a Phase-Separating Non-Solid Composition

A composition for tooth whitening was prepared from the followingingredients:

Eudragit L 100-55 6.99 g PVP30 14.97 g  PVP90 4.49 g Water 25.95 g Ethanol (95%) 28.94 g  PEG 3.99 g Eudragit RL 100 4.49 g Sodium citrate0.20 g Hydrogen peroxide 9.98 g

The composition was mixed in a Cole-Parmer high-torque low-speed labmixer supplied with Teflon coated impeller (2 inches in diameter) asfollows. PEG was mixed with ethanol. Eudragit RL 100 was dissolved inthe ethanol-PEG mixture, followed by the addition of Eudragit L 100-55.Sodium citrate was then added under stirring. Water was then added tothe mix followed by hydrogen peroxide and then PVP90 followed by PVP30,and allowed to mix for 2 hours. The solution was then stored over aperiod of 2-5 hours to let the air bubbles dissipate.

Example 11 Preparation of a Phase-Separating Non-Solid Composition

A composition for tooth whitening was prepared from the followingingredients and mixed as described in Example 9:

Eudragit L 100-55 4.99 g PVP30 12.97 g  PVP90 2.50 g Water 23.95 g Ethanol (95%) 26.95 g  PEG 7.98 g Eudragit RL 100 2.50 g Sodium citrate0.20 g Carbamide peroxide 17.96 g 

Example 12 In Vitro Release of Hydrogen Peroxide from a Phase-SeparatingNon-Solid Composition

Experiments were conducted in a manner similar to that set forth inExample 2 to evaluate the in vitro release of peroxide from the toothwhitening compositions of Examples 10 and 11. The formulations fromExamples 10 and 11 were found to provide relatively more sustainedrelease of peroxide as compared to a similar formulation that did notcontain Eudragit RL-100. The formulations from Examples 10 and 11 alsoprovided a more sustained profile compared to Colgate Simply White®product.

We claim:
 1. A phase separating, film-forming composition comprising: awater-swellable acrylate-based polymer, said polymer being insoluble inwater at a pH less than about 5.5; a blend of a poly(N-vinyl lactam)homopolymer and a complementary oligomer capable of hydrogen bonding tothe poly(N-vinyl lactam) homopolymer; a water-swellable cellulose esterpolymer, that is insoluble in water at all pH values; and an optionalactive agent, wherein upon exposure to an aqueous environment at a pH offrom about 6-8, the composition undergoes a phase separation wherein thewater-swellable cellulose ester polymer forms a film over the remainderof the composition comprising the water-swellable acrylate-based polymeror, the blend of the poly(N-vinyl lactam) homopolymer and complementaryoligomer and optional active agent; and wherein the weight ratio of theacrylate-based polymer to the cellulose ester polymer is within a rangeof about 1.5:1 to 2:1.
 2. The composition of claim 1, wherein thewater-swellable acrylate-based polymer is an acrylate-based polymer orcopolymer.
 3. The composition of claim 2, wherein the acrylate-basedpolymer or copolymer is selected from polymers and copolymers of acrylicacid, methacrylic acid, methyl acrylate, ethyl acrylate, methylmethacrylate, or ethyl methacrylate.
 4. The composition of claim 3,wherein the acrylate-based copolymer is a copolymer of methacrylic acidand ethyl acrylate.
 5. The composition of claim 1, wherein the celluloseester comprises monomer subunits selected from unesterified cellulosemonomer units, cellulose acetate monomer units, and either cellulosebutyrate monomer units or cellulose propionate monomer units.
 6. Thecomposition of claim 1, wherein the poly(N-vinyl lactam) homopolymer isselected from the group consisting of polyvinyl pyrrolidone, polyvinylcaprolactam, and blends thereof.
 7. The composition of claim 6, whereinthe poly(N-vinyl lactam) is polyvinyl pyrrolidone.
 8. The composition ofclaim 1, wherein the poly(N-vinyl lactam) homopolymer has a numberaverage molecular weight in a range of approximately 10,000 to2,000,000.
 9. The composition of claim 1, wherein the complementaryoligomer has a molecular weight in a range of about 45 to
 800. 10. Thecomposition of claim 9, wherein the complementary oligomer has amolecular weight in a range of about 45 to
 600. 11. The composition ofclaim 9, wherein the complementary oligomer is selected from the groupconsisting of polyalcohols, monomeric and oligomeric alkylene glycols,polyalkylene glycols, carboxyl-terminated polyalkylene glycols,amino-terminated polyalkylene glycols, ether alcohols, alkane diols andcarbonic diacids.
 12. The composition of claim 11, wherein thecomplementary oligomer is selected from the group consisting ofpolyethylene glycol and carboxyl-terminated polyethylene glycol.
 13. Thecomposition of claim 11, wherein the complementary oligomer ispolyethylene glycol.
 14. The composition of claim 1, wherein the activeagent is present and is a whitening agent selected from the groupconsisting of peroxides, metal chlorites, perborates, percarbonates,peresters, peroxyacids, and combinations thereof.
 15. The composition ofclaim 14, wherein the peroxide is selected from the group consisting ofhydrogen peroxide, calcium peroxide, carbamide peroxide, dialkylperoxides, diacyl peroxides, ketone peroxides, hydroperoxides, andmixtures thereof.
 16. The composition of claim 14, wherein the metalchlorite is selected from the group consisting of calcium chlorite,barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite,and potassium chlorite.
 17. The composition of claim 1, furthercomprising at least one additive selected from the group consisting offlavorants, sweeteners, fillers, preservatives, pH regulators,softeners, thickeners, colorants, pigments, dyes, refractive particles,flavorants, sweeteners, stabilizers, toughening agents, detackifiers,and permeation enhancers.
 18. The composition of claim 1, wherein thecomposition is translucent.
 19. The composition of claim 1, comprisingabout 0.1-60 wt % of an active agent.
 20. The composition of claim 1,comprising about 0.1-20 wt % of the water-swellable acrylate-basedpolymer, and the water-swellable water-insoluble cellulose esterpolymer; and about 1-30 wt % of the poly(N-vinyl lactam) homopolymer.21. The composition of claim 20, wherein the complementary oligomercomprises about 1-85 wt % of the poly(N-vinyl lactam)homopolymer/complementary oligomer blend.
 22. The composition of claim1, comprising about 1-30 wt % of the water-swellable acrylate-basedpolymer and the water-swellable water-insoluble cellulose ester polymer;and about 0.1-20 wt % of the poly(N-vinyl lactam) homopolymer.
 23. Thecomposition of claim 22, wherein the complementary oligomer comprisesabout 1-85 wt % of the poly(N-vinyl lactam) homopolymer/complementaryoligomer blend.
 24. The composition of claim 1, comprising about 1-20 wt% of the water-swellable acrylate-based polymer and the water-swellablewater-insoluble cellulose ester polymer; and about 20-80 wt % of thepoly(N-vinyl lactam) homopolymer.
 25. The composition of claim 24,wherein the complementary oligomer comprises about 10-80 wt % of thepoly(N-vinyl lactam) homopolymer/complementary oligomer blend.
 26. Thecomposition of claim 1, comprising about 20-80 wt % of thewater-swellable acrylate-based polymer, and the water-swellablewater-insoluble cellulose ester polymer; and about 1-20 wt % of thepoly(N-vinyl lactam) homopolymer.
 27. The composition of claim 26,wherein the complementary oligomer comprises about 10-80 wt % of thepoly(N-vinyl lactam) homopolymer/complementary oligomer blend.
 28. Thecomposition of claim 1, comprising a body-surface contactingcomposition, wherein upon application to a body surface and exposure toan aqueous environment at a pH of from about 6-8, the water-swellablecellulose ester polymer forms a water-permeable film over the remainderof the composition such that over time, dissolution of the underlyinglayer occurs.
 29. A method for whitening teeth comprising: applying thecomposition of claim 14 to at least a portion of the surface of one ormore teeth; and removing the composition when a desired degree ofwhitening has been achieved.
 30. The method of claim 29, wherein thedesired degree of whitening is achieved after a predetermined period oftime.
 31. The method of claim 30, wherein the predetermined period oftime is from about 10 minutes to about 24 hours.
 32. The method of claim31, wherein the predetermined period of time is from about 10 minutes toabout 8 hours.
 33. The method of claim 32, wherein the predeterminedperiod of time is about 30 minutes to 1 hour.